Functionalized pegylated cyanine compounds, pharmaceutical compositions, and methods of use thereof

ABSTRACT

Provided herein are functionalized pegylated cyanine compounds containing a reactive group suitable for labeling a biomolecule or pharmaceutical compositions and methods of use thereof. In one embodiment, the compounds are based on formula I shown below. 
                         
In other embodiments, the compounds can be pegylated at one or more of the following locations R 1 , R 4 , R 6 , R 9 , or L.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application No.62/276,462, filed on Jan. 8, 2016 and entitled, “FunctionalizedPegylated Cyanine Compunds, Pharmaceutical Compositions, and Methods ofuse Thereof.” The entire contents of the related application areincorporated by reference herein.

FIELD

Provided herein are functionalized pegylated cyanine compoundscontaining a reactive group suitable for labeling a biomolecule, andpharmaceutical compositions and methods of use thereof.

BACKGROUND

Cyanine dyes play an indispensable role in biomedical applications,particularly in fluorescence detection of antibodies and DNA, theimaging of biological targets in vivo, and fluorescent labelingcompounds for proteins. This is due to their excellent spectralproperties, including large molar extinction coefficients and broadwavelength tunabilities. The labeling of cyanine dyes to biomoleculesoften involves covalent conjugations in aqueous buffer solutions undermild conditions. However, planarity of the cyanine π system leads toaggregations and dimer formations in aqueous solution. Due toinsufficient hydrophilicity, non-specific interactions with varioussurfaces have been observed, resulting in problems with purifications ofthe corresponding cyanine-labeled bioconjugations, and an unsatisfactorysignal to noise ratio.

Functionalized polyethylene glycol (PEG) linkers with reactive groupsare important building blocks with a wide range of applications inbiochemical and pharmaceutical industries. PEG is non-toxic,non-immunogenic, non-antigenic, and highly soluble in water.Incorporations of functionalized PEG linkers into cyanine dyes not onlyimprove dye water solubility, but also introduce functionalities incyanine dyes for further conjugation with biomolecules.

SUMMARY OF THE DISCLOSURE

Provided herein is a compound of Formula I:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate, or hydrate thereof;wherein:

A is an anion bearing a negative charge;

L is

wherein:

-   -   each R^(L) is independently (a) hydrogen, deuterium, azido,        cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀        alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀        aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; or (c)        —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),        —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),        —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),        —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);    -   X^(a) is (a) hydrogen, deuterium, azido, cyano, halo, nitro,        oxo, sulfo, OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,        C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,        heteroaryl, or heterocyclyl , each of which is optionally        substituted with one or more substituents Q; (c)        —C(R^(1a)R^(1b)), —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),        —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),        —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),        —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c); (d) —(CH₂CH₂O)_(p)-L¹-Z¹,        —(CH₂CH₂O)_(p)—COOH, —(CH₂CH₂O)_(p)—N₃, —(CH₂CH₂O)_(p)—OH,        —(CH₂CH₂O)_(p)-alkyne, —(CH₂CH₂O)_(p)-biotin, —(CH₂CH₂O)_(p)-NHS        ester, —(CH₂CH₂O)_(p)-amine, —(CH₂CH₂O)_(p)-DBCO,        —(CH₂CH₂O)_(p)-Fmoc, —(CH₂CH₂O)_(p)-aldehyde,        —(CH₂CH₂O)_(p)-phosphonate, —(CH₂CH₂O)_(p)-tosylate,        —(CH₂CH₂O)_(p)-FPF ester, —(CH₂CH₂O)_(p)-Boc,        —(CH₂CH₂O)_(p)-aminooxy, —(CH₂CH₂O)_(p)-bromo,        —(CH₂CH₂O)_(p)-mal, or —(CH₂CH₂O)_(p)-propargyl; or (e)        carboxycylic acid, amine, azide, DBCO, hydrazide, maleimide, NHS        ester, TCO, tetrazine, or biotin;    -   m is an integer of 1, 2, or 3; and    -   n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;

X and Y are each independently C(R^(Xa)R^(Xb)), O, S, or NR^(Xc);

wherein:

-   -   R^(Xa) and R^(Xb) are each independently (a) hydrogen or        deuterium; or (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,        C_(3-hd 15) cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl,        or heterocyclyl; and    -   R^(Xc) is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀        aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),        —C(O)OR^(1a), —C(O)_(NR) ^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);

R¹ is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, orheterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or (d) —(CH₂CH₂O)_(p)-L¹-Z¹;

wherein:

-   -   L¹ is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene,        C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₁₋₁₀        heteroalkylene-C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀        aralkylene, heteroarylene, or heterocyclylene;    -   Z¹ is (a) amino, azido, chloro, bromo, iodo, or thiol; (b)        N-maleimido, N-3 ,4-dibromo-maleimido, C₂₋₆ alkynyl,        heterocyclyl containing a carbon-carbon triple, acrylyl,        3-sulfo-N-succinimidyloxycarbonyl, tetrafluorophenoxycarbonyl,        pentofluorophenoxycarbonyl, C₂₋₆ alkynyloxy, C₃₋₁₅ cycloalkyloxy        containing a carbon-carbon triple, C₆₋₂₀ aryloxy containing a        carbon-carbon triple, or heterocyclyloxy containing a        carbon-carbon triple; (c) —OP(OR^(1a))(NR^(1b)R^(1c)),        OP((NR^(1b)R^(1c))₂, —OS(O)₂R^(1a), or —S—SR^(1a); or (d) Z⁶;        and    -   p is an integer of 1 to 50;

R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, and R¹⁰ are each independently (a) hydrogen,deuterium, azido, cyano, halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b)C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl,C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —SR^(1a), —S(O)R^(1a),—S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); (d) R² and R³,R⁴ and R⁵, R⁷ and R⁸, or R⁹ and R¹⁰, each pair together with the carbonatoms to which they are attached independently form C₃₋₁₅ cycloalkyl,C₆₋₂₀ aryl, heteroaryl, or heterocyclyl; (e) R³ and R⁴, or R⁸ and R⁹,each pair together with the carbon atoms to which they are attachedindependently form C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, heteroaryl, orheterocyclyl; or (f) —O(CH₂CH₂O)_(r)-L^(r)-Z^(r), with the proviso thatwhen R¹ is not —(CH₂CH₂O)_(p)-L¹-Z¹, at least one of R¹, R², R³, R⁴, R⁵,R⁷, R⁸, R⁹, and R¹⁰ is —O(CH₂CH₂O)_(r)-L^(r)-Z^(r);

wherein:

-   -   L^(r) is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene,        C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₁₋₁₀        heteroalkylene-C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀        aralkylene, heteroarylene, or heterocyclylene;    -   Z^(r) is (a) hydrogen, deuterium, halo, cyano, nitro, sulfo,        —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,        heteroaryl, or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OC(O)R^(1a),        —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),        —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c),        —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d),        —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),        —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),        —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R6 ^(1c),        —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),        —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or (d) Z¹; and    -   r is an integer of 1 to 50;

R⁶ is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, orheterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); or (d) —(CH₂CH₂O)_(q)-L⁶-Z⁶;

wherein:

-   -   L⁶ is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene,        C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀        aralkylene, heteroarylene, or heterocyclylene;    -   Z⁶ is (a) hydrogen, deuterium, halo, cyano, nitro, sulfo,        —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,        heteroaryl, or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(≡0NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —IS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)Or^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a S(O)) ₂NR^(1b)R^(1c),        —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c); or (d) Z¹; and    -   q is an integer of 1 to 50; and

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently (a) hydrogen ordeuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; (c)R^(1a) and R^(1c) together with the C and N atoms to which they areattached form heterocyclyl; or (d) R^(1b) and R^(1c) together with the Natom to which they are attached form heteroaryl or heterocyclyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl,aralkylene, heteroaryl, heteroarylene, heterocyclyl, heterocyclylene,alkynyloxy, cycloalkyloxy, aryloxy, and heterocyclyloxy is optionallysubstituted with one or more substituents Q, where each Q isindependently selected from (a) deuterium, azido, cyano, halo, nitro,oxo, sulfo, —OPO₃H₂, and —PO₃H₂; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —CO (═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) deuterium, azido, cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, and—PO₃H₂; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g),—OR^(e), —OC(O)R^(e), —OC(O)OR^(e), —C(O)NR^(f)R^(g),—OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g),—OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e) S(O)R^(h),—NR^(e) S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e) S (O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heteroaryl or heterocyclyl.

Also provided herein is a compound of Formula I:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate, or hydrate thereof;wherein:

A is an anion bearing a negative charge;

L is

wherein:

-   -   each R^(L) is independently (a) hydrogen, deuterium, azido,        cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀        alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀        aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; or (c)        —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR_(1b)R^(1c),        (NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),        —OC(O)NR_(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),        —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),        —NR^(1b)R^(1c), —NR^(1a)C(O)R^(2d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C (═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(a1), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);    -   X^(a) is (a) hydrogen, deuterium, azido, cyano, halo, nitro,        oxo, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,        C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,        heteroaryl, or heterocyclyl , each of which is optionally        substituted with one or more substituents Q; (c)        —C(R^(1a)R^(1b)), —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),        —OC(O)NR^(1b)R^(1c), —OC(—NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),        —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),        —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR6 ^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)_(NR)        ^(1b)R^(1c)—SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),        —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); (d)        —(CH₂CH₂O)_(p)-L¹-Z¹, —(CH₂CH₂O)_(p)—COOH, 13 (CH₂CH₂O)_(p)—N₃,        —(CH₂CH₂O)_(p)—OH, —(CH₂CH₂O)_(p)-alkyne, —(CH₂CH₂O)_(p)-bionn,        —(CH₂CH₂O)_(p)-NHS ester, —(CH₂CH₂O)_(p)-amine,        —(CH₂CH₂O)_(p)-DBCO, —(CH₂CH₂O)_(p)-Fmoc,        —(CH₂CH₂O)_(p)-aldehyde, —(CH₂CH₂O)_(p)-phosphonate,        —(CH₂CH₂O)_(p)-tosylate, —(CH₂CH₂O)_(p)-FPF ester,        —(CH₂CH₂O)_(p)-Boc, —(CH₂CH₂O)_(p)-aminooxy,        —(CH₂CH₂O)_(p)-bromo, —(CH₂CH₂O)_(p)-mal, or        —(CH₂CH₂O)_(p)-propargyl; or (e) carboxycylic acid, amine,        azide, DBCO, hydrazide, maleimide, NHS ester, TCO, tetrazine, or        biotin;    -   m is an integer of 1, 2, or 3; and    -   n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;

X and Y are each independently C(R^(Xa)R^(Xb)), O, S, or NR^(Xc ;)

wherein:

-   -   R^(Xa) and R^(Xb) are each independently (a) hydrogen or        deuterium; or (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,        C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, or        heterocyclyl; and    -   R^(Xc) is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀        aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),        —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(a))NR^(1b)R^(1c),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        S(O)₂NR^(1b)R^(1c);

R¹ is —(CH₂CH₂O)_(p)-L¹-Z¹,

wherein:

-   -   L¹ is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene,        C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₁₋₁₀        heteroalkylene-C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀        aralkylene, heteroarylene, or heterocyclylene;    -   Z¹ is (a) amino, azido, chloro, bromo, iodo, or thiol; (b)        N-maleimido, N-3 ,4-dibromo-maleimido, C₂₋₆ alkynyl,        heterocyclyl containing a carbon-carbon triple, acrylyl,        3-sulfo-N-succinimidyloxycarbonyl, tetrafluorophenoxycarbonyl,        pentofluorophenoxycarbonyl, C₂₋₆ alkynyloxy, C₃₋₁₅ cycloalkyloxy        containing a carbon-carbon triple, C₆₋₂₀ aryloxy containing a        carbon-carbon triple, or heterocyclyloxy containing a        carbon-carbon triple; (c)        —OP(OR^(1a))(NR^(1b)R^(1c)),—OP((NR^(1b)R^(1c))₂, —OS(O)₂R^(1a),        or —S—SR^(1a); or (d) Z⁶; and    -   p is an integer of 1 to 50;

R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, and R¹⁰ are each independently (a) hydrogen,deuterium, azido, cyano, halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b)C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl,C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), (NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a)NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); (d) R² and R³, R⁴ and R⁵, R⁷and R⁸, or R⁹ and R¹⁰, each pair together with the carbon atoms to whichthey are attached independently form C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl,heteroaryl, or heterocyclyl; or (e) R³ and R⁴, or R⁸ and R⁹, each pairtogether with the carbon atoms to which they are attached independentlyform C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, heteroaryl, or heterocyclyl;

R⁶ is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, orheterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a)—S(O)NR^(1b)R^(1c)or—S(O)₂NR^(1b)R^(1c); or (d) —(CH₂CH₂O)_(q)-L⁶-Z⁶;

wherein:

-   -   L⁶ is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene,        C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀        aralkylene, heteroarylene, or heterocyclylene;    -   Z⁶ is (a) hydrogen, deuterium, halo, cyano, nitro, sulfo,        —OPO₂H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,        heteroaryl, or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR_(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c); or (d) z¹; and    -   q is an integer of 1 to 50; and

each R^(1a), R^(1c), and R^(1d) is independently (a) hydrogen ordeuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; (c)R^(1a) and R^(1c) together with the C and N atoms to which they areattached form heterocyclyl; or (d) R^(1b) and R^(1c) together with the Natom to which they are attached form heteroaryl or heterocyclyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl,aralkylene, heteroaryl, heteroarylene, heterocyclyl, heterocyclylene,alkynyloxy, cycloalkyloxy, aryloxy, and heterocyclyloxy is optionallysubstituted with one or more substituents Q, where each Q isindependently selected from (a) deuterium, azido, cyano, halo, nitro,oxo, sulfo, —OPO₃H₂, and —PO₃H₂; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) deuterium, azido, cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, and—PO₃H₂; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g),—OR^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)R^(e),—OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g),—OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heteroaryl or heterocyclyl.

Additionally provided herein is a pharmaceutical composition comprisinga compound disclosed herein, e.g., a compound of Formula I, or atautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; and apharmaceutically acceptable excipient.

Furthermore, provided herein is a method of labeling a biomolecule,comprising the step of contacting the biomolecule with a compounddisclosed herein, e.g., a compound of Formula I, or a tautomer or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable solvate or hydrate thereof.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inbiochemistry, biology, organic chemistry, medicinal chemistry,pharmaceutical chemistry, pharmacology, and others described herein arethose well known and commonly employed in the art. Unless definedotherwise, all technical and scientific terms used herein generally havethe same meaning as commonly understood by one of ordinary skill in theart to which this disclosure belongs.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 22nd ed.; Allen et al., Eds.; ThePharmaceutical Press, 2012; Handbook of Pharmaceutical Excipients, 7thed.; Rowe et al., Eds.; The Pharmaceutical Press: 2012; Handbook ofPharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower PublishingCompany: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.;Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkyl may optionally be substitutedwith one or more substituents Q as described herein. For example, C₁₋₆alkyl refers to a linear saturated monovalent hydrocarbon radical of 1to 6 carbon atoms or a branched saturated monovalent hydrocarbon radicalof 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linearsaturated monovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and branched C₃.₆ alkyl groups are also referred as “loweralkyl.” Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl (including all isomeric forms), n-propyl,isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl(including all isomeric forms).

The term “alkylene” refers to a linear or branched saturated divalenthydrocarbon radical, wherein the alkylene may optionally be substitutedwith one or more substituents Q as described herein. For example, C₁₋₆alkylene refers to a linear saturated divalent hydrocarbon radical of 1to 6 carbon atoms or a branched saturated divalent hydrocarbon radicalof 3 to 6 carbon atoms. In certain embodiments, the alkylene is a linearsaturated divalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15(C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated divalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and branched C₃₋₆ alkylene groups are also referred as“lower alkylene.” Examples of alkylene groups include, but are notlimited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (includingall isomeric forms), n-propylene (—CH₂CH₂CH₂—), isopropylene, butylene(including all isomeric forms), n-butylene (—CH₂CH₂CH₂CH₂—),isobutylene, t-butylene, pentylene (including all isomeric forms), andhexylene (including all isomeric forms).

The term “heteroalkylene” refers to a linear or branched saturateddivalent hydrocarbon radical that contains one or more heteroatoms eachindependently selected from O, S, and N in the hydrocarbon chain. Forexample, C₁₋₆ heteroalkylene refers to a linear saturated divalenthydrocarbon radical of 1 to 6 carbon atoms or a branched saturateddivalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the heteroalkylene is a linear saturated divalenthydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10(C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branched saturated divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ heteroalkylene groups are also referred as “lowerheteroalkylene.” Examples of heteroalkylene groups include, but are notlimited to, —CH₂O—, —CH₂OCH₂—, —(CH₂)₂O—, —(CH₂)₂OCH₂—, —CH₂NH—,—CH₂NHCH₂—, —(CH₂)₂NH—, —(CH₂)₂NHC(O)—, —(CH₂)₂NHC(O)CH₂—,—(CH₂)₂NHC(O)(CH₂)₂, —(CH₂)₂NHC(O)(CH₂)₃—, —(CH₂)₂NHC(O)(CH₂)₅—,—(CH₂)₆NHC(O)(CH₂)₂—, —(CH₂)₂NHC(O)(CH₂)₂C(O)—,—(CH₂)₂NHC(O)(CH₂)₄C(O)—, —(CH₂)₂C(O)NH(CH₂)₂C(O)—,—(CH₂)₂C(O)NH(CH₂)₄C(O)—, —(CH₂)₂NHC(O)CH(SO₃H)CH₂NHC(O)(CH₂)₂C(O)—,—(CH₂)₂C(O)NH(CH₂)₃—, —(CH₂)₂C(O)NH(CH₂)₄CH₂—, —CH₂S—, —CH₂CH₂—, and—CH₂CH₂S—. In certain embodiments, heteroalkylene may also be optionallysubstituted with one or more substituents Q as described herein.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more carbon-carbon double bond(s), in oneembodiment, one to five carbon-carbon double bond(s), in anotherembodiment, one carbon-carbon double bond. The alkenyl may be optionallysubstituted with one or more substituents Q as described herein. Theterm “alkenyl” embraces radicals having a “cis” or “trans” configurationor a mixture thereof, or alternatively, a “Z” or “E” configuration or amixture thereof, as appreciated by those of ordinary skill in the art.For example, C₂₋₆ alkenyl refers to a linear unsaturated monovalenthydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturatedmonovalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbonatoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀),3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms.Examples of alkenyl groups include, but are not limited to, ethenyl,propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more carbon-carbon doublebond(s), in one embodiment, one to five carbon-carbon double bond(s), inanother embodiment, one carbon-carbon double bond. The alkenylene may beoptionally substituted with one or more substituents Q as describedherein. The term “alkenylene” embraces radicals having a “cis” or“trans” configuration or a mixture thereof, or alternatively, a “Z” or“E” configuration or a mixture thereof, as appreciated by those ofordinary skill in the art. For example, C₂₋₆ alkenylene refers to alinear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atomsor a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkenylene is a linear divalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenylene groupsinclude, but are not limited to, ethenylene, allylene, propenylene,butenylene, and 4-methylbutenylene.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more carbon-carbon triple bond(s), in oneembodiment, one to five carbon-carbon triple bond(s), in anotherembodiment, one carbon-carbon triple bond. The alkynyl may be optionallysubstituted with one or more substituents Q as described herein. Forexample, C₂₋₆ alkynyl refers to a linear unsaturated monovalenthydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturatedmonovalent hydrocarbon radical of 4 to 6 carbon atoms. In certainembodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbonatoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C₃₋₂₀),4 to 15 (C₃₋₁₅), 4 to 10 (C₃₋₁₀), or 4 to 6 (C₃₋₆) carbon atoms.Examples of alkynyl groups include, but are not limited to, ethynyl(—C≡CH), propynyl (including all isomeric forms, e.g., 1-propynyl(—C≡CCH₃) and propargyl (—CH₂C≡CH)), butynyl (including all isomericforms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including allisomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), andhexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl).

The term “alkynylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more carbon-carbon triplebond(s), in one embodiment, one to five carbon-carbon triple bond(s), inanother embodiment, one carbon-carbon triple bond. The alkynylene may beoptionally substituted with one or more substituents Q as describedherein. For example, C₂₋₆ alkynylene refers to a linear unsaturateddivalent hydrocarbon radical of 2 to 6 carbon atoms or a branchedunsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. Incertain embodiments, the alkynylene is a linear divalent hydrocarbonradical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched divalent hydrocarbon radical of 4 to20 (C₃₋₂₀), 4 to 15 (C₃₋₁₅), 4 to 10 (C₃₋₁₀), or 4 to 6 (C₃₋₆) carbonatoms. Examples of alkynylene groups include, but are not limited to,ethynylene (—C≡C—), propynylene (including all isomeric forms, e.g.,1,3-propynylene (—C≡CCH₂—)), butynylene (including all isomeric forms,e.g., 1-butyn-1,4-ylene), pentynylene (including all isomeric forms,e.g., 1-pentyn-1,5-ylene), and hexynylene (including all isomeric forms,e.g., 1-hexyn-1,6-ylene).

The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical,which may be optionally substituted with one or more substituents Q asdescribed herein. In one embodiment, cycloalkyl groups may be saturatedor unsaturated but non-aromatic, and/or bridged, and/or non-bridged,and/or fused bicyclic groups. In certain embodiments, the cycloalkyl hasfrom 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), orfrom 3 to 7 (C₃₋₇) carbon atoms. Examples of cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl,cycloheptenyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, andadamantyl.

The term “cycloalkylene” refers to a cyclic divalent hydrocarbonradical, which may be optionally substituted with one or moresubstituents Q as described herein. In one embodiment, cycloalkylenegroups may be saturated or unsaturated but non-aromatic, and/or bridged,and/or non-bridged, and/or fused bicyclic groups. In certainembodiments, the cycloalkylene has from 3 to 20 (C₃₋₂₀), from 3 to 15(C₃₋₁₅), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms.Examples of cycloalkylene groups include, but are not limited to,cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene,cyclohexylene, cyclohexenylene, cyclohexadienylene, cycloheptylene,cycloheptenylene, bicyclo[2.1.1]hexylene, bicyclo[2.2.1]heptylene,decalinylene, and adamantylene.

The term “aryl” refers to a monovalent monocyclic aromatic group and/ormonovalent polycyclic aromatic group that contain at least one aromaticcarbon ring. In certain embodiments, the aryl has from 6 to 20 (C₆₋₂₀),from 6 to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms. Examples ofaryl groups include, but are not limited to, phenyl, naphthyl,fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, andterphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, whereone of the rings is aromatic and the others of which may be saturated,partially unsaturated, or aromatic, for example, dihydronaphthyl,indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certainembodiments, aryl may be optionally substituted with one or moresubstituents Q as described herein.

The term “arylene” refers to a divalent monocyclic aromatic hydrocarbonradical or divalent polycyclic aromatic hydrocarbon radical thatcontains at least one aromatic hydrocarbon ring. In certain embodiments,the arylene has from 6 to 20 (C₆₋₂₀), from 6 to 15 (C₆₋₁₅), or from 6 to10 (C₆₋₁₀) ring atoms. Examples of arylene groups include, but are notlimited to, phenylene, naphthylene, fluorenylene, azulenylene,anthrylene, phenanthrylene, pyrenylene, biphenylene, and terphenylene.Arylene also refers to bicyclic or tricyclic carbon rings, where one ofthe rings is aromatic and the others of which may be saturated,partially unsaturated, or aromatic, for example, dihydronaphthylene,indenylene, indanylene, or tetrahydronaphthylene (tetralinylene). Incertain embodiments, arylene may be optionally substituted with one ormore substituents Q as described herein.

The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl groupsubstituted with one or more aryl groups. In certain embodiments, thearalkyl has from 7 to 30 (C₇₋₃₀), from 7 to 20 (C₇₋₂₀), or from 7 to 16(C₇₋₁₆) carbon atoms. Examples of aralkyl groups include, but are notlimited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certainembodiments, aralkyl are optionally substituted with one or moresubstituents Q as described herein.

The term “aralkylene” or “arylalkylene” refers to a divalent alkylenegroup substituted with one or more aryl groups. In certain embodiments,the aralkylene has from 7 to 30 (C₇₋₃₀), from 7 to 20 (C₇₋₂₀), or from 7to 16 (C₇₋₁₆) carbon atoms. Examples of aralkylene groups include, butare not limited to, benzylene, 2-phenylethylene, and 3-phenylpropylene.In certain embodiments, aralkylene are optionally substituted with oneor more substituents Q as described herein.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupor monovalent polycyclic aromatic group that contain at least onearomatic ring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, and N in the ring.Heteroaryl groups are bonded to the rest of a molecule through thearomatic ring. Each ring of a heteroaryl group can contain one or two Oatoms, one or two S atoms, and/or one to four N atoms; provided that thetotal number of heteroatoms in each ring is four or less and each ringcontains at least one carbon atom. In certain embodiments, theheteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.Examples of monocyclic heteroaryl groups include, but are not limitedto, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl,pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, andtriazolyl. Examples of bicyclic heteroaryl groups include, but are notlimited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl,benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl,benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl,indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl,isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl,pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl,thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclicheteroaryl groups include, but are not limited to, acridinyl,benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl,phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may alsobe optionally substituted with one or more substituents Q as describedherein.

The term “heteroarylene” refers to a divalent monocyclic aromatic groupor divalent polycyclic aromatic group that contains at least onearomatic ring, wherein at least one aromatic ring contains one or moreheteroatoms in the ring, each of which is independently selected from O,S, and N. A heteroarylene group has at least one linkage to the rest ofa molecule via its aromatic ring(s). Each ring of a heteroarylene groupcan contain one or two O atoms, one or two S atoms, and/or one to four Natoms, provided that the total number of heteroatoms in each ring isfour or less and each ring contains at least one carbon atom. In certainembodiments, the heteroarylene has from 5 to 20, from 5 to 15, or from 5to 10 ring atoms. Examples of monocyclic heteroarylene groups include,but are not limited to, furanylene, imidazolylene, isothiazolylene,isoxazolylene, oxadiazolylene, oxadiazolylene, oxazolylene,pyrazinylene, pyrazolylene, pyridazinylene, pyridylene, pyrimidinylene,pyrrolylene, thiadiazolylene, thiazolylene, thienylene, tetrazolylene,triazinylene, and triazolylene. Examples of bicyclic heteroarylenegroups include, but are not limited to, benzofuranylene,benzimidazolylene, benzoisoxazolylene, benzopyranylene,benzothiadiazolylene, benzothiazolylene, benzothienylene,benzotriazolylene, benzoxazolylene, furopyridylene, imidazopyridinylene,imidazothiazolylene, indolizinylene, indolylene, indazolylene,isobenzofuranylene, isobenzothienylene, isoindolylene, isoquinolinylene,isothiazolylene, naphthyridinylene, oxazolopyridinylene,phthalazinylene, pteridinylene, purinylene, pyridopyridylene,pyrrolopyridylene, quinolinylene, quinoxalinylene, quinazolinylene,thiadiazolopyrimidylene, and thienopyridylene. Examples of tricyclicheteroarylene groups include, but are not limited to, acridinylene,benzindolylene, carbazolylene, dibenzofuranylene, perimidinylene,phenanthrolinylene, phenanthridinylene, phenarsazinylene, phenazinylene,phenothiazinylene, phenoxazinylene, and xanthenylene. In certainembodiments, heteroarylene may also be optionally substituted with oneor more substituents Q as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalentmonocyclic non-aromatic ring system or monovalent polycyclic ring systemthat contains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, and N; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. Heterocyclyl groups are bonded to the rest of a moleculethrough the non-aromatic ring. In certain embodiments, the heterocyclylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay be fused or bridged, and in which nitrogen or sulfur atoms may beoptionally oxidized, nitrogen atoms may be optionally quaternized, andsome rings may be partially or fully saturated, or aromatic. Theheterocyclyl may be attached to the main structure at any heteroatom orcarbon atom which results in the creation of a stable compound. Examplesof such heterocyclic groups include, but are not limited to, azepinyl,benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl,benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl,cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl,dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl,furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also beoptionally substituted with one or more substituents Q as describedherein.

The term “heterocyclylene” refers to a divalent monocyclic non-aromaticring system or divalent polycyclic ring system that contains at leastone non-aromatic ring, wherein one or more of the non-aromatic ringatoms are heteroatoms independently selected from O, S, and N; and theremaining ring atoms are carbon atoms. Heterocyclylene groups are bondedto the rest of a molecule through the non-aromatic ring. In certainembodiments, the heterocyclylene group has from 3 to 20, from 3 to 15,from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. Incertain embodiments, the heterocyclylene is a monocyclic, bicyclic,tricyclic, or tetracyclic ring system, which may be fused or bridged,and in which nitrogen or sulfur atoms may be optionally oxidized,nitrogen atoms may be optionally quaternized, and some rings may bepartially or fully saturated, or aromatic. The heterocyclylene may beattached to the main structure at any heteroatom or carbon atom whichresults in the creation of a stable compound. Examples of suchheterocyclylene groups include, but are not limited to, azepinylene,benzodioxanylene, benzodioxolylene, benzofuranonylene,benzopyranonylene, benzopyranylene, benzotetrahydrofuranylene,benzotetrahydrothienylene, benzothiopyranylene, benzoxazinylene,β-carbolinylene, chromanylene, chromonylene, cinnolinylene,coumarinylene, decahydroisoquinolinylene, dihydrobenzisothiazinylene,dihydrobenzisoxazinylene, dihydrofurylene, dihydroisoindolylene,dihydropyranylene, dihydropyrazolylene, dihydropyrazinylene,dihydropyridinylene, dihydropyrimidinylene, dihydropyrrolylene,dioxolanylene, 1,4-dithianylene, furanonylene, imidazolidinylene,imidazolinylene, indolinylene, isobenzotetrahydrofuranylene,isobenzotetrahydrothienylene, isochromanylene, isocoumarinylene,isoindolinylene, isothiazolidinylene, isoxazolidinylene, morpholinylene,octahydroindolylene, octahydroisoindolylene, oxazolidinonylene,oxazolidinylene, oxiranylene, piperazinylene, piperidinylene,4-piperidonylene, pyrazolidinylene, pyrazolinylene, pyrrolidinylene,pyrrolinylene, quinuclidinylene, tetrahydrofurylene,tetrahydroisoquinolinylene, tetrahydropyranylene, tetrahydrothienylene,thiamorpholinylene, thiazolidinylene, tetrahydroquinolinylene, and1,3,5-trithianylene. In certain embodiments, heterocyclic may also beoptionally substituted with one or more substituents Q as describedherein.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group orsubstituent, such as an alkyl, alkylene, heteroalkylene, alkenyl,alkenylene, alkynyl, cycloalkyl, cycloalkylene, aryl, aryl ene, aralkyl,aralkylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylenegroup, may be substituted with one or more sub stituents Q, each ofwhich is independently selected from, e.g., (a) deuterium, azido (—N₃),cyano (—CN), halo, nitro (NO₂), oxo (═O), sulfo (—SO₃H), —PO₃H₂, and—OPO₃H₂, (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each of whichis further optionally substituted with one or more, in one embodiment,one, two, three, or four, substituents Q^(a); and (c) —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OS(O)R^(a), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c); wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); or (iii) R^(b) and R^(c) together with the N atom to which theyare attached form heteroaryl or heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a). As used herein, all groups that canbe substituted are “optionally substituted,” unless otherwise specified.

In one embodiment, each Q^(a) is independently selected from the groupconsisting of (a) deuterium, azido, halo, cyano, nitro, oxo, sulfo,—OPO₃H₂, and —PO₃H₂; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and(c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g),—OC^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g),—OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g),—OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h),—NR^(e)C(O)NR^(f)R^(g), —BR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R_(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heteroaryl or heterocyclyl.

The terms “substantially pure” and “substantially homogeneous” meansufficiently homogeneous to appear free of readily detectable impuritiesas determined by standard analytical methods used by one of ordinaryskill in the art, including, but not limited to, thin layerchromatography (TLC), gel electrophoresis, high performance liquidchromatography (HPLC), gas chromatography (GC), nuclear magneticresonance (NMR), mass spectrometry (MS), and elemental analysis; orsufficiently pure such that further purification would not detectablyalter the physical, chemical, biological, and/or pharmacologicalproperties, such as enzymatic and biological activities, of thesubstance. In certain embodiments, “substantially pure” or“substantially homogeneous” refers to a collection of molecules, whereinat least about 50%, at least about 70%, at least about 80%, at leastabout 90%, at least about 95%, at least about 98%, at least about 99%,or at least about 99.5% by weight of the molecules are a singlecompound, including a single tautomer or a mixture of tautomers, asdetermined by standard analytical methods.

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which present in stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage or recognized abbreviations including abbreviationsfound in J. Org. Chem. 2007, 72, 23A-24A or abbreviations established bythe IUPAC-IUB Commission on Biochemical Nomenclature (Biochem. 1972, 11,942-944).

Compounds

In one embodiment, provided herein is a compound of Formula I:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate, or hydrate thereof;wherein:

A is an anion bearing a negative charge;

L is

wherein:

-   -   each R^(L) is independently (a) hydrogen, deuterium, azido,        cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀        alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀        aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; or (c)        —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),        —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),        —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),        —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a)—S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);    -   X^(a) is (a) hydrogen, deuterium, azido, cyano, halo, nitro,        oxo, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,        C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,        heteroaryl, or heterocyclyl , each of which is optionally        substituted with one or more substituents Q; (c)        —C(R^(1a)R^(1b)), —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),        —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),        —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),        —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂MR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)_(NR)        ^(1b)R^(1c);(d) —(CH₂CH₂O)_(p)-L¹-Z¹, —(CH₂CH₂O)_(p)—COOH,        —(CH₂CH₂O)_(p)—N₃, —(CH₂CH₂O)_(p)—OH, —(CH₂CH₂O)_(p)-alkyne,        —(CH₂CH₂O)_(p)-biotin, —(CH₂CH₂O)_(p)-NHS ester,        —(CH₂CH₂O)_(p)-amine, —(CH₂CH₂O)_(p)-DBCO, —(CH₂CH₂O)_(p)-Fmoc,        —(CH₂CH₂O)_(p)-aldehyde, —(CH₂CH₂O)_(p)-phosphonate,        —(CH₂CH₂O)_(p)-tosylate, —(CH₂CH₂O)_(p)-FPF ester,        —(CH₂CH₂O)_(p)-Boc, —(CH₂CH₂O)_(p)-aminooxy,        —(CH₂CH₂O)_(p)-bromo, —(CH₂CH₂O)_(p)-mal, or        —(CH₂CH₂O)_(p)-propargyl; or (e) carboxycylic acid, amine,        azide, DBCO, hydrazide, maleimide, NHS ester, TCO, tetrazine, or        biotin;    -   m is an integer of 1, 2, or 3; and    -   n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;

X and Y are each independently C(R^(Xa)R^(Xb)), O, S, or NR^(Xc);

wherein:

-   -   R^(Xa) and R^(Xb) are each independently (a) hydrogen or        deuterium; or (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,        C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, or        heterocyclyl; and    -   R^(Xc) is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀        aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),        —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),        —S(O)R_(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);

R¹ is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, orheterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a)NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); or (d) —(CH₂CH₂O)_(p)-L¹-Z¹;

wherein:

-   -   L¹ is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene,        C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₁₋₁₀        beteroalkylene-C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀        aralkylene, heteroarylene, or heterocyclylene;    -   Z¹ is (a) amino, azido, chloro, bromo, iodo, or thiol; (b)        N-maleimido, N-3,4-dibromo-maleimido, C₂₋₆ alkynyl, heterocyclyl        containing a carbon-carbon triple, acrylyl,        3-sulfo-N-succinimidyloxycarbonyl, tetrafluorophenoxycarbonyl,        pentofluorophenoxycarbonyl, C₂₋₆ alkynyloxy, C₃₋₁₅ cycloalkyloxy        containing a carbon-carbon triple, C₆₋₂₀ aryloxy containing a        carbon-carbon triple, or heterocyclyloxy containing a        carbon-carbon triple; (c) —OP(OR^(1a))(NR^(1b)R^(1a)),        —OP((NR^(1b)R^(1c))₂, —OS(O)₂R^(1a), or —S—SR^(1a); or (d) Z⁶;        and    -   p is an integer of 1 to 50;

R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, and R¹⁰ are each independently (a) hydrogen,deuterium, azido, cyano, halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b)C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl,C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(N^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R¹, —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); (d) R² and R³, R⁴ and R⁵, R⁷and R⁸, or R⁹ and R¹⁰, each pair together with the carbon atoms to whichthey are attached independently form C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl,heteroaryl, or heterocyclyl; (e) R³ and R⁴, or R⁸ and R⁹, each pairtogether with the carbon atoms to which they are attached independentlyform C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, heteroaryl, or heterocyclyl; or (f)—O(CH₂CH₂O)_(r)-L^(r)-Z^(r), with the proviso that when R¹ is not—(CH₂CH₂O)_(p)-L¹-Z¹, at least one of R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹,and R¹⁰, is —O(CH₂CH₂O)_(r)-L^(r)-Z^(r);

wherein:

-   -   L^(r) is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene,        C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₁₋₁₀        heteroalkylene-C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀        aralkylene, heteroarylene, or heterocyclylene;    -   Z^(r) is (a) hydrogen, deuterium, halo, cyano, nitro, sulfo,        —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,        heteroaryl, or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c); or (d) Z¹; and    -   r is an integer of 1 to 50;

R⁶ is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, orheterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c)or —S(O)₂NR^(1b)R^(1c); or (d) —(CH₂CH₂O)_(q)-L⁶-Z⁶;

wherein:

-   -   L⁶ is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene,        C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀        aralkylene, heteroarylene, or heterocyclylene;    -   Z⁶ is (a) hydrogen, deuterium, halo, cyano, nitro, sulfo,        —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,        heteroaryl, or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR_(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c); or (d) Z¹; and    -   q is an integer of 1 to 50; and

each R^(1a), is independently (a) hydrogen or deuterium; (b) C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀aralkyl, heteroaryl, or heterocyclyl; (c) R^(1a) and R^(1c) togetherwith the C and N atoms to which they are attached form heterocyclyl; or(d) R^(1b) and R^(1c) together with the N atom to which they areattached form heteroaryl or heterocyclyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl,aralkylene, heteroaryl, heteroarylene, heterocyclyl, heterocyclylene,alkynyloxy, cycloalkyloxy, aryloxy, and heterocyclyloxy is optionallysubstituted with one or more substituents Q, where each Q isindependently selected from (a) deuterium, azido, cyano, halo, nitro,oxo, sulfo, —OPO₃H₂, and —PO₃H₂; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) deuterium, azido, cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, and—PO₃H₂; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g),—OR^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g),—OC(═NR^(c))NR^(f)R^(g), —OS(O)R^(c), —OS(O)₂R^(c), —OS(O)NR^(f)R^(g),—OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C⁷⁻¹⁵ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heteroaryl or heterocyclyl.

-   -   In another embodiment, provided herein is a compound of Formula        I:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof;wherein:

A is an anion bearing a negative charge;

L is

wherein:

-   -   each R^(L) is independently (a) hydrogen, deuterium, azido,        cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀        alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀        aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; or (c)        —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —OR^(la), —OC(O)R^(1a), —OC(O)OR^(1a),    -   —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),        —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),        —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);    -   X^(a) is (a) hydrogen deuterium, azido, cyano, halo, nitro, oxo,        sulfo, —OPO₃H₂, or —PO₃H²; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,        heteroaryl, or heterocyclyl, each of which is optionally        substituted with one or more substituents Q; (c) —C(R^(1a)        R^(1b)), —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),        —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),        —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),        —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),        —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c); (d) —(CH₂CH₂O)_(p)-L¹-Z¹,        —(CH₂CH₂O)_(p)—COOH, —(CH₂CH₂O)_(p), —N₃, —(CH₂CH₂O)_(p)—OH,        —(CH₂CH₂O)_(p)-alkyne, —(CH₂CH₂O)_(p)-biotin, —(CH₂CH₂O)_(p)-NHS        ester, —(CH₂CH₂O)_(p)-amine, —(CH₂CH₂O)_(p)-DBCO,        —(CH₂CH₂O)_(p)-Fmoc, —(CH₂CH₂O)_(p)-aldehyde,        —(CH₂CH₂O)_(p)-phosphonate, —(CH₂CH₂O)_(p)-tosylate,        —(CH₂CH₂O)_(p)-FPF ester, —(CH₂CH₂O)_(p)-Boc,        -(CH₂CH₂O)_(p)-aminooxy, —(CH₂CH₂O)_(p)-bromo,        —(CH₂CH₂O)_(p)-mal, or —(CH₂CH₂O)_(p)-propargyl; or (e)        carboxycylic acid, amine, azide, DBCO, hydrazide, maleimide, NHS        ester, TCO, tetrazine, or biotin;    -   m is an integer of 1, 2, or 3; and    -   n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;

X and Y are each independently C(R^(Xa)R^(Xb)), O, S, or NR^(Xc);

wherein:

-   -   R^(Xa) and R^(Xb) are each independently (a) hydrogen or        deuterium; or (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,        C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, or        heterocyclyl; and    -   R^(Xc) is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀        aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),        —C(O)OR^(1a), —C(O)NR_(1b)R_(1c), —C(NR^(1a))NR^(1b)R^(1c),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c);

R¹ is —(CH₂CH₂O)_(p)-L¹-Z¹,

wherein:

-   -   L¹ is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene,        C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₁₋₁₀        heteroalkylene-C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀        aralkylene, heteroarylene, or heterocyclylene;    -   Z¹ is (a) amino, azido, chloro, bromo, iodo, or thiol; (b)        N-maleimido, N-3,4-dibromo-maleimido, C₂₋₆ alkynyl, heterocyclyl        containing a carbon-carbon triple, acrylyl,        3-sulfo-N-succinimidyloxycarbonyl, tetrafluorophenoxycarbonyl,        pentofluorophenoxycarbonyl, C₂₋₆ alkynyloxy, C₃₋₁₅ cycloalkyloxy        containing a carbon-carbon triple, C₆₋₂₀ aryloxy containing a        carbon-carbon triple, or heterocyclyloxy containing a        carbon-carbon triple; (c)        —OP(OR^(1a))(NR^(1b)R^(1c))—OP((NR^(1b)R^(1c))₂, —OS(O)₂R^(1a),        or —S—SR^(1a); or (d) Z⁶; and    -   p is an integer of 1 to 50;

R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, and R¹⁰ are each independently (a) hydrogen,deuterium, azido, cyano, halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b)C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl,C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c)—OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); (d) R² and R³, R⁴ and R⁴ andR⁵, R⁷ and R⁸, or R⁹ and R¹⁰, each pair together with the carbon atomsto which they are attached independently form C₃₋₁₅ cycloalkyl, C₆₋₂₀aryl, heteroaryl, or heterocyclyl; or (e) R³ and R⁴, or R⁸ and R⁹, eachpair together with the carbon atoms to which they are attachedindependently form C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, heteroaryl, orheterocyclyl;

R⁶ is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, orheterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c) —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c)or —S(O)₂NR^(1b)R^(1c); or (d) —(CH₂CH₂O)_(q)-L⁶-Z⁶;

wherein:

-   -   L⁶ is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene,        C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀        aralkylene, heteroarylene, or heterocyclylene;    -   Z⁶ is (a) hydrogen, deuterium, halo, cyano, nitro, sulfo,        —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,        heteroaryl, or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a),        —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),        —OR(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),        —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),        —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),        —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),        —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),        —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d),        —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),        —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or        —S(O)₂NR^(1b)R^(1c); or (d) Z¹; and    -   q is an integer of 1 to 50; and

each R^(1a), K is independently (a) hydrogen or deuterium; (b) C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀aralkyl, heteroaryl, or heterocyclyl; (c) R^(1a) and R^(1c) togetherwith the C and N atoms to which they are attached form heterocyclyl; or(d) R^(1b) and R^(1c) together with the N atom to which they areattached form heteroaryl or heterocyclyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl,aralkylene, heteroaryl, heteroarylene, heterocyclyl, heterocyclylene,alkynyloxy, cycloalkyloxy, aryloxy, and heterocyclyloxy is optionallysubstituted with one or more substituents Q, where each Q isindependently selected from (a) deuterium, azido, cyano, halo, nitro,oxo, sulfo, —OPO₃H₂, and —PO₃H₂; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) deuterium, azido, cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, and—PO₃H₂; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g),—OR^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g),—OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g),—OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h), isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heteroaryl or heterocyclyl.

In yet another embodiment, provided herein is a compound Formula II:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R^(g), R⁹, R¹⁰, A, X, Y, and m are , each as definedherein.

In one embodiment, in Formula I or II, R⁶ is (a) hydrogen; (b) C₁₋₁₀alkyl, optionally substituted with one or more substituents Q; or (c)—(CH₂CH₂O)_(q)-L⁶-Z⁶, where L⁶, Z⁶, and q are each as defined herein. Inanother embodiment, in Formula I or II, R⁶ is C₁₋₁₀ alkyl, optionallysubstituted with one or more substituents Q. In yet another embodiment,in Formula I or II, R⁶ is methyl or propyl, each of which is optionallysubstituted with one or more substituents Q. In yet another embodiment,in Formula I or II, R⁶ is methyl or 3-hydroxypropyl. In still anotherembodiment, in Formula I or II, R⁶ is (CH₂CH₂O)_(q)-L⁶-Z⁶, where L⁶, Z⁶,and q are each as defined herein.

In one embodiment, in Formula I or II, one of R², R³, R⁴, and R⁵ is nothydrogen and the remaining three are each hydrogen. In anotherembodiment, in Formula I or II, R², R³, R⁴, and R⁵ are each hydrogen. Inyet another embodiment, in Formula I or II, one of R⁷, R⁸, R⁹, and R¹⁰is not hydrogen and the remaining three are each hydrogen. In stillanother embodiment, in Formula I or II, R⁷, R⁸, R⁹, and R¹⁰ are eachhydrogen.

In one embodiment, in Formula I or II, R¹ is —(CH₂CH₂O)_(p)L¹-Z¹, whereL⁻, Z¹, and p are each as defined herein. In another embodiment, inFormula I or II, R⁴ is —O(CH₂CH₂O)_(r)-L^(r)-Z^(r), where If, Z^(r), andr are each as defined herein. In yet another embodiment, in in Formula Ior II, R⁹ is —O(CH₂CH₂O)_(r)-L^(r)Z^(r), where L^(r), Z^(r), and r areeach as defined herein.

In one embodiment, in Formula I or II, R¹ is —(CH₂CH₂O)_(p)-L¹-Z¹ and R⁴is —O(CH₂CH₂O)_(r)-L^(r)-Z^(r), where L^(l), L^(r), Z^(l), Z^(r), p, andr are each as defined herein. In another embodiment, in Formula I or II,R¹ is —(CH₂CH₂O)_(p)-L¹-Z¹ and R⁹ is —O (CH₂CH₂O)_(r)-L^(r)-Z^(r), whereL^(l), L^(r), Z¹, Z^(r), p, and r are each as defined herein. In yetanother embodiment, in Formula I or II, R⁴ and R⁹ are each independently—O(CH₂CH₂O)_(r)-L^(r)-Z^(r), where 12^(.), Z^(r), and r are each asdefined herein. In still another embodiment, in Formula I or II, R¹ is(CH₂CH₂O)_(p)-L¹-Z¹, and R⁴ and R⁹ are each independently—O(CH₂CH₂O)_(r)-L^(r)-Z^(r), where L¹, L^(r), Z^(l), Z^(r), p, and r areeach as defined herein.

In yet another embodiment, provided herein is a compound Formula III:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof;wherein:

R^(x) and R^(Y) are each independently (a) hydrogen, deuterium, azido,cyano, halo, nitro, sulfo, —OPO₃H₂, or PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and

A, L¹, L⁶, R^(1a), R^(1b), R^(1c), R^(1d), X, Y, Z¹, Z⁶, m, p, and q areeach as defined herein.

In one embodiment, in Formula I, II, or III, R² and R³, or R⁴ and R⁵,each pair together with the carbon atoms to which they are attachedindependently form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q. In another embodiment, in Formula I, II, or III, R² andR³, or R⁴ and R⁵, each pair together with the carbon atoms to which theyare attached independently form C₆₋₂₀ aryl, optionally substituted withone or more substituents Q. In yet another embodiment, in Formula I, II,or III, R³ and R⁴ together with the carbon atoms to which they areattached independently form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q. In still another embodiment, in Formula I, II, or III,R³ and R⁴ together with the carbon atoms to which they are attachedindependently form C₆₋₂₀ aryl, optionally substituted with one or moresubstituents Q.

In one embodiment, in Formula I, II, or III, R⁷ and R⁸, or R⁹ and R¹⁰,each pair together with the carbon atoms to which they are attachedindependently form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q. In another embodiment, in Formula I, II, or III, R⁷ andR⁸, or R⁹ and R¹⁰, each pair together with the carbon atoms to whichthey are attached independently form C₆₋₂₀ aryl, optionally substitutedwith one or more substituents Q. In yet another embodiment, in FormulaI, II, or III, R^(g) and R⁹ together with the carbon atoms to which theyare attached independently form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q. In still another embodiment, in Formula I, II, orIII, R⁸ and R⁹ together with the carbon atoms to which they are attachedindependently form C₆₋₂₀ aryl, optionally substituted with one or moresubstituents Q.

In vet another embodiment, provided herein is a compound Formula IV:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(X),R^(Y), A, L₁, L⁶, X, Y, Z¹, Z⁶m, p, and q are each as defined herein.

In one embodiment, in any one of Formulae Ito IV, m is an integer of 1.In another embodiment, in any one of Formulae III or IV, m is an integerof 2. In yet another embodiment, in any one of Formulae I to IV, m is aninteger of 3.

In one embodiment, in Formula III or IV, R^(Y) is hydrogen or sulfo. Inanother embodiment, in Formula III or IV, R^(Y) is hydrogen or sulfo.

In yet another embodiment, provided herein is a compound of Formula V:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(L), A, X, Y, and n are each asdefined herein.

In one embodiment, in Formula V, R⁶ is (a) hydrogen; (b) C₁₋₁₀ alkyl,optionally substituted with one or more substituents Q; or (c)—(CH₂CH₂O)_(q)L⁶-Z⁶, where L⁶, Z⁶, and q are each as defined herein. Inanother embodiment, in Formula V, R⁶ is C₁₋₁₀ alkyl, optionallysubstituted with one or more substituents Q. In yet another embodiment,in Formula V, R⁶ is methyl or propyl, each of which is optionallysubstituted with one or more substituents Q. In still anotherembodiment, in Formula V, R⁶ is methyl or 3-hydroxypropyl.

In one embodiment, in Formula V, one of R², R³, R⁴, and R⁵ is nothydrogen and the remaining three are each hydrogen. In anotherembodiment, in Formula V, R², R³, R⁴, and R⁵ are each hydrogen. In yetanother embodiment, in Formula V, one of R⁷, R⁸, R⁹, and R¹⁰ is nothydrogen and the remaining three are each hydrogen. In still anotherembodiment, in Formula V, R⁷, R⁸, R⁹, and R¹⁰ are each hydrogen.

In one embodiment, in Formula V, R² and R³, or R⁴ and R⁵, each pairtogether with the carbon atoms to which they are attached independentlyform C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q. Inanother embodiment, in Formula V, R² and R³, or R⁴ and R⁵, each pairtogether with the carbon atoms to which they are attached independentlyform C₆₋₂₀ aryl, optionally substituted with one or more substituents Q.In yet another embodiment, in Formula V, R³ and R⁴ together with thecarbon atoms to which they are attached independently form C₃₋₇cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q. In still anotherembodiment, in Formula V, R³ and R⁴ together with the carbon atoms towhich they are attached independently form C₆₋₂₀ aryl, optionallysubstituted with one or more substituents Q.

In one embodiment, in Formula V, R⁷ and R⁸, or R⁹ and R¹⁰, each pairtogether with the carbon atoms to which they are attached independentlyform C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q. Inanother embodiment, in Formula V, R⁷ and R⁸, or R⁹ and R¹⁰, each pairtogether with the carbon atoms to which they are attached independentlyform C₆₋₂₀ aryl, optionally substituted with one or more substituents Q.In yet another embodiment, in Formula V, R⁸ and R⁹ together with thecarbon atoms to which they are attached independently form C₃₋₇cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q. In still anotherembodiment, in Formula V, R⁸ and R⁹ together with the carbon atoms towhich they are attached independently form C₆₋₂₀ aryl, optionallysubstituted with one or more substituents Q.

In yet another embodiment, provided herein is a compound Formula VI:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(L),R^(X), R^(Y), L¹, L⁶, Z¹, Z⁶, A, X, Y, n, p, and q are each as definedherein.

In yet another embodiment, provided herein is a compound Formula VII:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(L),R^(X), R^(Y), A, L¹, L⁶, X, Y, Z⁶, Z⁶, n, p, and q are each as definedherein.

In one embodiment, in any one of Formulae I and V to VII, n is aninteger of 0. In another embodiment, in any one of Formulae I and V toVII, n is an integer of 1. In yet another embodiment, in any one ofFormulae I and V to VII, n is an integer of 2.

In one embodiment, in Formula VI or VII, R^(L) is halo. In anotherembodiment, in Formula VI or VII, R^(L) is fluoro or chloro. In yetanother embodiment, in Formula VI or VII, R^(L) is chloro.

In one embodiment, in Formula VI or VII, R^(X) is hydrogen or sulfo. Inanother embodiment, in Formula VI or VII, R^(Y) is hydrogen or sulfo.

In one embodiment, in any one of Formulae I to VII, X isC(R^(Xa)R^(Xb)), S, or O, where R^(Xa) and R^(Xb) are each as definedherein. In another embodiment, in any one of Formulae I to VII, X isC(CH₃), C(CH₃)₂, S, or O. In yet another embodiment, in any one ofFormulae I to VII, Xis C(CH₃)₂. In yet another embodiment, in any one ofFormulae I to VII, X is S. In yet another embodiment, in any one ofFormulae I to VII, X is O.

In one embodiment, in any one of Formulae I to VII, U is C(R^(Xa)R^(Xb))S, or O, where R^(Xa) and R^(Xb) are each as defined herein. In anotherembodiment, in any one of Formulae I to VII, Y is C(CH₃), C(CH₃)₂, S, orO. In yet another embodiment, in any one of Formulae I to VII, Y isC(CH₃)₂. In yet another embodiment, in any one of Formulae Ito VII, Y isS. In yet another embodiment, in any one of Formulae Ito VII, Y is O.

In one embodiment, in any one of Formulae Ito VII, X and Y are eachindependently C(R^(Xa)R^(Xb)), S, or O, where R^(Xa) and R^(Xb) are eachas defined herein. In another embodiment, in any one of Formulae I toVII, X and Y are C(CH₃), C(CH₃)₂, S, or O. In yet another embodiment, inany one of Formulae Ito VII, X and Y are C(CH₃)₂. In yet anotherembodiment, in any one of Formulae Ito VII, X and Y are S. In yetanother embodiment, in any one of Formulae Ito VII, X and Y are O.

In yet another embodiment, provided herein is a compound Formula VIII:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, A and L are each as defined herein.

In yet another embodiment, provided herein is a compound Formula IX:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof wherein R¹, R²,R³R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, A, and m are each as defined herein.

In one embodiment, in Formula VIII or IX, R⁶ is (a) hydrogen; (b) C₁₋₁₀alkyl, optionally substituted with one or more substituents Q; or (c)—(CH₂CH₂O)_(q)-L⁶-Z⁶, where L⁶, Z⁶, and q are each as defined herein. Inanother embodiment, in Formula VIII or IX, R⁶ is C₁₋₁₀ alkyl, optionallysubstituted with one or more substituents Q. In yet another embodiment,in Formula VIII or IX, R⁶ is methyl or propyl, each of which isoptionally substituted with one or more substituents Q. In still anotherembodiment, in Formula VIII or IX, R⁶ is methyl or 3-hydroxypropyl.

In one embodiment, in Formula VIII or IX, one of R², R³, R⁴, and R⁵ isnot hydrogen and the remaining three are each hydrogen. In anotherembodiment, in Formula VIII or IX, R², R³, R⁴, and R⁵ are each hydrogen.In yet another embodiment, in Formula VIII or IX, one of R⁷, R⁸, R⁹, andR¹⁰ is not hydrogen and the remaining three are each hydrogen. In stillanother embodiment, in Formula VIII or IX, R⁷, R⁸, R⁹, and R¹⁰ are eachhydrogen.

In one embodiment, in Formula VIII or IX, R² and R³, or R⁴ and R⁵, eachpair together with the carbon atoms to which they are attachedindependently form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q. In another embodiment, in Formula VIII or IX, R² and R³,or R⁴ and R⁵, each pair together with the carbon atoms to which they areattached independently form C₆₋₂₀ aryl, optionally substituted with oneor more substituents Q. In yet another embodiment, in Formula VIII orIX, R³ and R⁴ together with the carbon atoms to which they are attachedindependently form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q. In still another embodiment, in Formula VIII or IX, R³and R⁴ together with the carbon atoms to which they are attachedindependently form C₆₋₂₀ aryl, optionally substituted with one or moresubstituents Q.

In one embodiment, in Formula VIII or IX, R⁷ and R⁸, or R⁹ and R¹⁰, eachpair together with the carbon atoms to which they are attachedindependently form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q. In another embodiment, in Formula VIII or IX, R⁷ and R⁸,or R⁹ and R¹⁰, each pair together with the carbon atoms to which theyare attached independently form C₆₋₂₀ aryl, optionally substituted withone or more substituents Q. In yet another embodiment, in Formula VIIIor IX, R⁸ and R⁹ together with the carbon atoms to which they areattached independently form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q. In still another embodiment, in Formula VIII or IX, R⁸and R⁹ together with the carbon atoms to which they are attachedindependently form C₆₋₂₀ aryl, optionally substituted with one or moresubstituents Q.

In yet another embodiment, provided herein is a compound Formula X:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(X),R^(Y), L¹, L⁶, L¹, Z⁶, A, m, p, and q are each as defined herein.

In yet another embodiment, provided herein is a compound Formula XI:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(X),R^(Y), L¹, L⁶, Z¹, Z⁶, A, m, p, and q are each as defined herein.

In one embodiment, in any one of Formulae VIII to XI, m is an integerof 1. In another embodiment, in any one of Formulae VIII to XI, m is aninteger of 2. In yet another embodiment, in any one of Formulae VIII toXI, m is an integer of 3.

In one embodiment, in Formula X or XI, R^(X) is hydrogen or sulfo. Inanother embodiment, in Formula X or XI, R^(Y) is hydrogen or sulfo.

In yet another embodiment, provided herein is a compound of Formula XII:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰R^(L), R^(L), X^(a), A, and n are , eachas defined herein.

In one embodiment, in Formula XII, R⁶ is (a) hydrogen; (b) C₁₋₁₀ alkyl,optionally substituted with one or more substituents Q; or (c)—(CH₂CH₂O)_(q)-L⁶-Z⁶, where L⁶, Z⁶, and q are each as defined herein. Inanother embodiment, in Formula XII, R⁶ is C₁₋₁₀ alkyl, optionallysubstituted with one or more substituents Q. In yet another embodiment,in Formula XII, R⁶ is methyl or propyl, each of which is optionallysubstituted with one or more substituents Q. In yet another embodiment,in Formula XII, R⁶ is methyl or 3-hydroxypropyl. In still anotherembodiment, in Formula XII, R⁶ is —(CH₂CH₂O)_(q)-L⁶-Z⁶, where L⁶, Z⁶,and q are each as defined herein.

In one embodiment, in Formula XII, one of R², R³, R⁴, and R⁵ is nothydrogen and the remaining three are each hydrogen. In anotherembodiment, in Formula XII, R², R³, R⁴, and R⁵ are each hydrogen. In yetanother embodiment, in Formula XII, one of R⁷, R⁸, R⁹, and R¹⁰ is nothydrogen and the remaining three are each hydrogen. In still anotherembodiment, in Formula XII, R⁷, R⁸, R⁹, and R¹⁰ are each hydrogen.

In one embodiment, in Formula XII, R² and R³, or R⁴ and R⁵, each pairtogether with the carbon atoms to which they are attached independentlyform C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q. Inanother embodiment, in Formula XII, R² and R³, or R⁴ and R⁵, each pairtogether with the carbon atoms to which they are attached independentlyform C₆₋₂₀ aryl, optionally substituted with one or more substituents Q.In yet another embodiment, in Formula XII, R³ and R⁴ together with thecarbon atoms to which they are attached independently form C₃₋₇cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q. In still anotherembodiment, in Formula XII, R³ and R⁴ together with the carbon atoms towhich they are attached independently form C₆₋₂₀ aryl, optionallysubstituted with one or more substituents Q.

In one embodiment, in Formula XII, R⁷ and R⁸, or R⁹ and R¹⁰, each pairtogether with the carbon atoms to which they are attached independentlyform C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q. Inanother embodiment, in Formula XII, R⁷ and R⁸, or R⁹ and R¹⁰, each pairtogether with the carbon atoms to which they are attached independentlyform C₆₋₂₀ aryl, optionally substituted with one or more substituents Q.In yet another embodiment, in Formula XII, R⁸ and R⁹ together with thecarbon atoms to which they are attached independently form C₃₋₇cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q. In still anotherembodiment, in Formula XII, R⁸ and R⁹ together with the carbon atoms towhich they are attached independently form C₆₋₂₀ aryl, optionallysubstituted with one or more substituents Q.

In yet another embodiment, provided herein is a compound Formula XIII:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(L),R^(X), R^(Y), A, L¹, L⁶, Z¹, Z⁶, n, p, and q are each as defined herein.

In still another embodiment, provided herein is a compound Formula XIV:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(L),R^(X), R^(Y), A, L¹, L⁶, Z¹, Z⁶, n, p, and q are each as defined herein.

In one embodiment, in any one of Formulae XII to XIV, n is an integer of0. In another embodiment, in any one of Formulae XII to XIV, n is aninteger of 1. In yet another embodiment, in any one of Formulae XII toXIV, n is an integer of 2.

In one embodiment, in any one of Formulae XII to XIV, R^(L) is halo. Inanother embodiment, in any one of Formulae XII to XIV, R^(L) is fluoroor chloro. In yet another embodiment, in any one of Formulae XII to XIV,R^(L) is chloro.

In one embodiment, in Formula XIII or XIV, R^(X) is hydrogen or sulfo.In another embodiment, in Formula XIII or XIV, R^(Y) is hydrogen orsulfo.

In yet another embodiment, provided herein is a compound Formula XV:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein: R^(X),R^(Y), L¹, L⁶, Z¹, Z₆, A, X, m, p, and q are each as defined herein.

In still another embodiment, provided herein is a compound Formula XVa:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(X),R^(y) L¹, L⁶, Z¹, Z⁶, A, m, p, and q are each as defined herein.

In still another embodiment, provided herein is a compound Formula XVb:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(X),R^(Y), L¹, L⁶, Z¹, Z⁶, A, m, p, and q are each as defined herein.

In still another emobidment, provided herein is a compound Formula XVI:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R¹, R⁶,R^(X), R^(Y) and m are each as defined herein.

In one embodiment, provided herein is a compound Formula XVIa:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R⁶, A,m, and p are each as defined herein.

In another embodiment, provided herein is a compound Formula XVIb:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R⁶, A,m, and p are each as defined herein.

In yet another embodiment, provided herein is a compound Formula XVIc:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R⁶, A,m, and p are each as defined herein.

In yet another embodiment, provided herein is a compound Formula XVId:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R⁶, A,m, and p are each as defined herein.

In still another embodiment, provided herein is a compound Formula XVIe:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R⁶, A,m, and p are each as defined herein.

In still another emobidment, provided herein is a compound Formula XVIf:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R⁶, A,m, and p are each as defined herein. Z is (a) hydrogen, deuterium, halo,O, S, N, or Se; (b) Z¹ or Z⁶; or (c) R^(Xc)Z¹, R^(Xa)R^(Xc)Z¹, R^(Xc)Z⁶,R^(Xa)R^(Xc)Z⁶, C(R^(Xa)R^(Xb)), or NR^(Xc), wherein R^(Xa), R^(Xb),R^(Xc), Z¹, and Z⁶ are each as defined herein.

In still another emobidment, provided herein is a compound Formula XVIg:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R⁶, A,Z, m, and p are each as defined herein.

In still another emobidment, provided herein is a compound Formula XVII:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R¹, R⁶,R^(X), R^(Y) and m are each as defined herein

In yet another embodiment, provided herein is a compound Formula XVIII:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R¹, R⁶,A, and m are each as defined herein. R^(9a) and R^(4a) are independently(a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; (c) —R1a, —OR1a, NR1bR1c, —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —C(═NR^(1a))NR^(1b)R^(1c),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), —S(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), or (d) —(CH₂CH₂O)_(q)-L¹-Z¹; wherein R^(1a),R^(1b), R^(1c), L¹, Z¹, Q, and q are each as defined herein

In yet another embodiment, provided herein is a compound Formula XIX:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(L), X^(a), A, Z, and n are each asdefined herein.

In yet another embodiment, provided herein is a compound Formula XIXa:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(L), R^(a), A and n are each asdefined herein.

In yet another embodiment, provided herein is a compound Formula XIXb:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(L), X^(a), A and n are each asdefined herein.

In yet another embodiment, provided herein is a compound Formula XIXc:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(X),R^(Y), L¹, L⁶, Z¹, Z⁶, X^(a), A, Z, n, p, and q arfe each as definedherein.

In yet another embodiment, provided herein is a compound Formula XX:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(X),R^(Y), L¹, L⁶, A, Z, m, p, and q are each as defined herein.

In yet another embodiment, provided herein is a compound Formula XXa:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(X),R^(Y), L¹, L⁶, Z¹, Z⁶, A, m, p, and q are each as defined herein.

In yet another embodiment, provided herein is a compound Formula XXb:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(X),R^(Y), L¹, L⁶, Z¹, Z⁶, A, m, p, and q are each as defined herein.

In yet another embodiment, provided herein is a compound Formula XXc:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein R^(X),R^(Y), L¹, L⁶, Z¹, Z⁶, A, m, p, and q are each as defined herein.

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,each functional group or constituent is as shown below.

Ref Functional Group/Constituent A an anion bearing a negative charge L

R^(L) (a) hydrogen, deuterium, azido, cyano, halo, nitro, oxo, sulfo,—OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c) X^(a) (a) hydrogen,deuterium, azido, cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, or —PO₃H₂;(b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; , each of which isoptionally substituted with one or more substituents Q; (c)—C(R^(1a)R^(1b)), —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); (d) —(CH₂CH₂O)_(p)—L¹—Z¹,—(CH₂CH₂O)_(p)—COOH, —(CH₂CH₂O)_(p)—N₃, —(CH₂CH₂O)_(p)—OH,—(CH₂CH₂O)_(p)-alkyne, —(CH₂CH₂O)_(p)-biotin, —(CH₂CH₂O)_(p)-NHS ester,—(CH₂CH₂O)_(p)-amine, —(CH₂CH₂O)_(p)-DBCO, —(CH₂CH₂O)_(p)-Fmoc,—(CH₂CH₂O)_(p)-aldehyde, —(CH₂CH₂O)_(p)-phosphonate,—(CH₂CH₂O)_(p)-tosylate, —(CH₂CH₂O)_(p)-FPF ester, —(CH₂CH₂O)_(p)-Boc,—(CH₂CH₂O)_(p)-aminooxy, —(CH₂CH₂O)_(p)-bromo, —(CH₂CH₂O)_(p)-mal, or—(CH₂CH₂O)_(p)-propargyl; or (e) carboxycylic acid, amine, azide, DBCO,hydrazide, maleimide, NHS ester, TCO, tetrazine, or biotin m integer of1, 2, or 3 n integer of 0, 1, 2, 3, 4, 5, 6, or 7 X C(R^(Xa)R^(Xb)), O,S, or NR^(Xc) Y C(R^(Xa)R^(Xb)), O, S, or NR^(Xc) R^(Xa) (a) hydrogen ordeuterium; or (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl;R^(Xb) (a) hydrogen or deuterium; or (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl,or heterocyclyl; R^(Xc) (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R¹ (a) hydrogen ordeuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);or (d) —(CH₂CH₂O)_(p)—L¹—Z¹ L¹ C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene,C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, C₁₋₁₀heteroalkylene-C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀ aralkylene,heteroarylene, or heterocyclylene Z¹ (a) amino, azido, chloro, bromo,iodo, or thiol; (b) N-maleimido, N-3,4-dibromo-maleimido, C₂₋₆ alkynyl,heterocyclyl containing a carbon-carbon triple, acrylyl,3-sulfo-N-succinimidyloxycarbonyl, tetrafluorophenoxycarbonyl,pentofluorophenoxycarbonyl, C₂₋₆ alkynyloxy, C₃₋₁₅ cycloalkyloxycontaining a carbon-carbon triple, C₆₋₂₀ aryloxy containing a carbon-carbon triple, or heterocyclyloxy containing a carbon-carbon triple; (c)—OP(OR^(1a))(NR^(1b)R^(1c)), —OP((NR^(1b)R^(1c))₂, —OS(O)₂R^(1a), or—S—SR^(1a); or (d) Z⁶ p integer of 1 to 50 R², R³, independently (a)hydrogen, deuterium, azido, cyano, halo, nitro, sulfo, —OPO₃H₂, or R⁴,R⁵, —PO₃H₂; R⁷, R⁸, (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, R⁹, heteroaryl, or heterocyclyl;and (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), R¹⁰ —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); (d) R² and R³, R⁴ and R⁵, R⁷and R⁸, or R⁹ and R¹⁰, each pair together with the carbon atoms to whichthey are attached independently form C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl,heteroaryl, or heterocyclyl; (e) R³ and R⁴, or R⁸ and R⁹, each pairtogether with the carbon atoms to which they are attached independentlyform C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, heteroaryl, or heterocyclyl; or (f)—O(CH₂CH₂O)_(r)—L^(r)—Z^(r), with the proviso that when R¹ is not—(CH₂CH₂O)_(p)—L¹—Z¹, at least one of R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹,and R¹⁰ is —O(CH₂CH₂O)_(r)—L^(r)—Z^(r) L^(r) C₁₋₁₀ alkylene, C₁₋₁₀heteroalkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene,C₁₋₁₀ heteroalkylene-C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀aralkylene, heteroarylene, or heterocyclylene Z^(r) (a) hydrogen,deuterium, halo, cyano, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀aralkyl, heteroaryl, or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or (d) Z¹ r integer of 1 to50 R⁶ (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, orheterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); or (d) —(CH₂CH₂O)_(q)—L⁶—Z⁶ L⁶ C₁₋₁₀ alkylene,C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene, C₃₋₁₅cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀ aralkylene, heteroarylene, orheterocyclylene Z⁶ (a) hydrogen, deuterium, halo, cyano, nitro, sulfo,—OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or (d) Z¹ q integer of 1 to50 R^(1a), independently (a) hydrogen or deuterium; R^(1b), (b) C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀aralkyl, R^(1c), heteroaryl, or heterocyclyl; and (c) R^(1a) and R^(1c)together with the C and N atoms to which they are attached form R^(1d)heterocyclyl; or (d) R^(1b) and R^(1c) together with the N atom to whichthey are attached form heteroaryl or heterocyclyl Q independently (a)deuterium, azido, cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, and —PO₃H₂;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c) R^(a), R^(b),independently (a) hydrogen or deuterium; R^(c), and (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, R^(d)heteroaryl, or heterocyclyl, each of which is further optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q^(a); or (c) R^(b) and R^(c) together with the Natom to which they are attached form heteroaryl or heterocyclyl, each ofwhich is further optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a) Q^(a) (a)deuterium, azido, cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, and —PO₃H₂;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e),—OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g),—OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g),—NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g) R^(e), R^(f), independently (a) hydrogen or deuterium;R^(g), (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, and heteroaryl, or heterocyclyl; or R^(h) (c)R^(f) and R^(g) together with the N atom to which they are attached formheteroaryl or heterocyclyl R^(X) independently (a) hydrogen, deuterium,azido, cyano, halo, nitro, sulfo, —OPO₃H₂, and —PO₃H₂; R^(Y) (b) C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀aralkyl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one or more substituents Q; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), -S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c) Z (a) hydrogen, deuterium,halo, O, S, N, or Se; (b) Z¹ or Z⁶; or (c) R^(Xc)Z¹, R^(Xa)R^(Xc)Z¹,R^(Xc)Z⁶, R^(Xa)R^(Xc)Z⁶, C(R^(Xa)R^(Xb)), or NR^(Xc) R^(9a)independently (a) hydrogen or deuterium; and (b) C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,R^(4a) heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one or more substituents Q; (c) —R1a, —OR1a, —NR1bR1c,—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—C(═NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), —S(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), or (d) —(CH₂CH₂O)_(q)—L¹—Z¹

In one embodiment, in any one of the formulae provided herein, includingFormulae I to XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa toXXc, A is an anion of acetic acid, 2,2-dichloroacetic acid, acylatedamino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(15)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronicacid, L-glutamic acid, a-oxoglutaric acid, glycolic acid, hippuric acid,hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid,(±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid,(−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonicacid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid,phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid,4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid, undecylenic acid, and valeric acid.

In another embodiment, in any one of the formulae provided herein,including Formulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, andXXa to XXc, A is fluoride (F), chloride (Cr), bromide (Br⁻), iodide (F),acetate (CH₃CO₂ ⁻), phosphate (PO₄H₂ ⁻, PO₄H²⁻, or PO₄ ³⁻), or sulfate(SO₄ ⁻or SO₄ ²⁻). In yet another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, A is chloride.

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,L¹ is C₁₋₁₀ alkylene, optionally substituted with one or moresubstituents Q. In another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, L¹ is methylene, ethylene, propylene,butylenes, pentylene, or hexylene, each of which is optionallysubstituted with one or more substituents Q. In yet another embodiment,in any one of the formulae provided herein, including Formulae Ito XX,XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc, L¹ is methylene,1,2-ethylene, 1,3-propylene, 1,4-butylenes, 1,5-pentylene, or1,6-hexylene, each optionally substituted with one or more substituentsQ. In still another embodiment, in any one of the formulae providedherein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa toXIXc, and XXa to XXc, L¹ is methylene, 1,2-ethylene, or 1,3-propylene.

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,L¹ is C₁₋₁₀ heteroalkylene, optionally substituted with one or moresubstituents Q. In another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, L¹ is (CH₂)₂O—, —(CH₂)₂OCH₂−, —CH₂NH—,—CH₂NHCH₂, —(CH₂)₂NH—, —(CH₂)₂NHC(O)—, —(CH₂)₂NHC(O)CH₂—,—(CH₂)₂NHC(O)(CH₂)₂—, —(CH₂)₂NHC(O)(CH₂)₃—, —(CH₂)₂NHC(O)(CH₂)₅—,—(CH₂)₆NHC(O)(CH₂)₂—, —(CH₂)₂NHC(O)(CH₂)₂C(O)—,—(CH₂)₂NHC(O)(CH₂)₄C(O)—, —(CH₂)₂C(O)NH(CH₂)₂C(O)—,—(CH₂)₂C(O)NH(CH₂)₄C(O)—, —(CH₂)₂NHC(O)CH(SO₃H)CH₂NHC(O)(CH₂)₂C(O)—,—(CH₂)₂C(O)NH(CH₂)₃—, or —(CH₂)₂C(O)NH(CH₂)₄CH₂—.

In one embodiment, in any one of the formulae provided herein, includingFormulae I to XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa toXXc, L¹ is C₁₋₁₀ heteroalkylene-C₃₋₁₅ cycloalkylene, where theheteroalkylene and cycloalkylene are each independently and optionallysubstituted with one or more substituents Q.

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,Z¹ is C₂₋₆ alkynyl, optionally substituted with one or more substituentsQ. In another embodiment, in any one of the formulae provided herein,including Formulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, andXXa to XXc, Z¹ is heterocyclyl containing a carbon-carbon triple,optionally substituted with one or more substituents Q. In yet anotherembodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,Z¹ is C₂₋₆ alkynyloxy, optionally substituted with one or moresubstituents Q. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z¹ is C₃₋₁₅ cycloalkyloxy containing acarbon-carbon triple, optionally substituted with one or moresubstituents Q. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z¹ is C₆₋₂₀ aryloxy containing acarbon-carbon triple, optionally substituted with one or moresubstituents Q. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z¹ is heterocyclyloxy containing acarbon-carbon triple, optionally substituted with one or moresubstituents Q. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae I to XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z¹ is —OP(OR^(1a))(NR^(1b)R^(1c)), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In yet anotherembodiment, in any one of the formulae provided herein, includingFormulae I to XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa toXXc, Z₁ is —OP((NR^(1b)R^(1c))₂, wherein R^(1b) and R^(1c) are each asdefined herein. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae I to XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z¹ is —OS(O)₂R^(1a), wherein R^(1a) is asdefined herein. In still another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z¹ is SSR^(1a), wherein R^(1a) is asdefined herein.

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,Z¹ is:

In another embodiment, in any one of the formulae provided herein,including Formulae I to XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, andXXa to XXc, L¹-Z¹ is:

In one embodiment, in any one of the formulae provided herein, includingFormulae I to XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa toXXc, p is an integer from 1 to 20. In another embodiment, in any one ofthe formulae provided herein, including Formulae Ito XX, XVa to XVb,XVIa to XVIg, XIXa to XIXc, and XXa to XXc, p is an integer of 1, 2, 3,4, 5, 6, 7, 8, 9, or 10. In yet another embodiment, in any one of theformulae provided herein, including Formulae Ito XX, XVa to XVb, XVIa toXVIg, XIXa to XIXc, and XXa to XXc, p is an integer of 5, 10, 15, 20,25, 30, 35, 40, 45, or 50.

L⁶ is C₁₋₁₀ alkylene, optionally substituted with one or moresubstituents Q. In another embodiment, in any one of the formulaeprovided herein, including Formulae I to XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, L⁶ is methylene, ethylene, propylene,butylenes, pentylene, or hexylene, each of which is optionallysubstituted with one or more substituents Q. In yet another embodiment,in any one of the formulae provided herein, including Formulae Ito XX,XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc, L⁶ is methylene,1,2-ethylene, 1,3-propylene, 1,4-butylenes, 1,5-pentylene, or1,6-hexylene, each optionally substituted with one or more substituentsQ. In still another embodiment, in any one of the formulae providedherein, including Formulae I to XX, XVa to XVb, XVIa to XVIg, XIXa toXIXc, and XXa to XXc, L⁶ is methylene, 1,2-ethylene, or 1,3-propylene.

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,L⁶ is C₁₋₁₀ alkylene, optionally substituted with one or moresubstituents Q. In another embodiment, in any one of the formulaeprovided herein, including Formulae I to XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, L⁶ is methylene, ethylene, propylene,butylenes, pentylene, or hexylene, each of which is optionallysubstituted with one or more substituents Q. In yet another embodiment,in any one of the formulae provided herein, including Formulae I to XX,XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc, L⁶ is methylene,1,2-ethylene, 1,3-propylene, 1,4-butylenes, 1,5-pentylene, or1,6-hexylene, each optionally substituted with one or more substituentsQ. In still another embodiment, in any one of the formulae providedherein, including Formulae I to XX, XVa to XVb, XVIa to XVIg, XIXa toXIXc, and XXa to XXc, L⁶ is methylene, 1,2-ethylene, or 1,3-propylene.

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,L⁶ is C₁₋₁₀ heteroalkylene, optionally substituted with one or moresubstituents Q. In another embodiment, in any one of the formulaeprovided herein, including Formulae I to XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, L⁶ is —(CH₂)₂O—, —(CH₂)₂OCH₂—, —CH₂NH—,—CH₂NHCH₂—, —(CH₂)₂NG—, —(CH₂)₂NHC(O)—, —(CH₂)₂NHC(O)CH₂—, —(CH₂₂NHC(O)(CH₂)₂—, —(CH₂)₂NHC(O)(CH₂)₃—, —(CH₂)₂NHC(O)(CH₂)₅)—,—(CH₂)₆NHC(O)(CH₂)₂—, —(CH₂)₂NHC(O)(CH₂)₂C(O)—, —(CH₂)₂NHC(O)(CH₂₄C(O)—, —(CH₂)₂C(O)NH(CH₂)₂C(O)—, —(CH₂)₂C(O)NH(CH₂)₄C(O)—,—(CH₂)₂NHC(O)CH(SO₃H)CH₂NHC(O)(CH₂)₂C(O)—, —(CH₂)₂C(O)NH(CH₂)₃—, or—(CH₂)₂C(O)NH(CH₂)₄CH₂—.

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,L⁶ is C₁₋₁₀ heteroalkylene-C₃₋₁₅ cycloalkylene, where the heteroalkyleneand cycloalkylene are each independently and optionally substituted withone or more substituents Q.

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,Z⁶ is hydrogen. In another embodiment, in any one of the formulaeprovided herein, including Formulae I to XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z⁶ is C₁₋₁₀ alkyl, optionally substitutedwith one or more substituents Q. In yet another embodiment, in any oneof the formulae provided herein, including Formulae Ito XX, XVa to XVb,XVIa to XVIg, XIXa to XIXc, and XXa to XXc, Z⁶ is methyl. In yet anotherembodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,Z⁶ is —C(O)R^(1a), wherein R^(1a) is as defined herein. In yet anotherembodiment, in any one of the formulae provided herein, includingFormulae I to XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa toXXc, Z⁶ is —C(O)CH₃. In yet another embodiment, in any one of theformulae provided herein, including Formulae Ito XX, XVa to XVb, XVIa toXVIg, XIXa to XIXc, and XXa to XXc, Z⁶ is C(O)OR^(1a), wherein R^(1a) isas defined herein. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae I to XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z⁶ is —C(O)OH or C(O)OtBU. In yet anotherembodiment, in any one of the formulae provided herein, includingFormulae I to XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa toXXc, Z⁶ is —C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each asdefined herein. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z⁶ is —C(O)NH₂. In yet another embodiment,in any one of the formulae provided herein, including Formulae I to XX,XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc, Z⁶ is—NR_(1b)R^(1c), wherein R^(1b) and R^(1c) are each as defined herein. Inyet another embodiment, in any one of the formulae provided herein,including Formulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, andXXa to XXc, Z⁶ is —NHCH₃. In yet another embodiment, in any one of theformulae provided herein, including Formulae I to XX, XVa to XVb, XVIato XVIg, XIXa to XIXc, and XXa to XXc, Z⁶ is —NR^(1a)C(O)R^(1d), whereinR^(1b) and R^(1c) are each as defined herein. In still anotherembodiment, in any one of the formulae provided herein, includingFormulae I to XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa toXXc, Z⁶ is —NHBoc.

In one embodiment, in any one of the formulae provided herein, includingFormulae I to XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa toXXc, Z⁶ is C₂₋₆ alkynyl, optionally substituted with one or moresubstituents Q. In another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z⁶ is heterocyclyl containing acarbon-carbon triple, optionally substituted with one or moresubstituents Q. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z⁶ is C₂₋₆ alkynyloxy, optionallysubstituted with one or more substituents Q. In yet another embodiment,in any one of the formulae provided herein, including Formulae Ito XX,XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc, Z⁶ is C₃₋₁₅cycloalkyloxy containing a carbon-carbon triple, optionally substitutedwith one or more substituents Q. In yet another embodiment, in any oneof the formulae provided herein, including Formulae Ito XX, XVa to XVb,XVIa to XVIg, XIXa to XIXc, and XXa to XXc, Z⁶ is C₆₋₂₀ aryloxycontaining a carbon-carbon triple, optionally substituted with one ormore substituents Q. In yet another embodiment, in any one of theformulae provided herein, including Formulae Ito XX, XVa to XVb, XVIa toXVIg, XIXa to XIXc, and XXa to XXc, Z⁶ is heterocyclyloxy containing acarbon-carbon triple, optionally substituted with one or moresubstituents Q. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z⁶ is —OP(OR^(1a))(NR^(1b)R^(1c)), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In yet anotherembodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,Z⁶ is —OP((NR^(1b)R^(1c))₂, wherein R^(1b) and R^(1c) are each asdefined herein. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z⁶ is —OS(O)₂R^(1a), wherein R^(1a) is asdefined herein. In still another embodiment, in any one of the formulaeprovided herein, including Formulae I to XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, Z⁶ is SSR^(1a), wherein R^(1a) is asdefined herein.

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,Z⁶ is:

In another embodiment, in any one of the formulae provided herein,including Formulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, andXXa to XXc, L⁶-Z⁶ is:

In one embodiment, in any one of the formulae provided herein, includingFormulae Ito XX, XVa to XVb, XVIa to XVIg, XIXa to XIXc, and XXa to XXc,q is an integer from 1 to 20. In another embodiment, in any one of theformulae provided herein, including Formulae Ito XX, XVa to XVb, XVIa toXVIg, XIXa to XIXc, and XXa to XXc, q is an integer of 1, 2, 3, 4, 5, 6,7, 8, 9, or 10. In yet another embodiment, in any one of the formulaeprovided herein, including Formulae Ito XX, XVa to XVb, XVIa to XVIg,XIXa to XIXc, and XXa to XXc, q is an integer of 5, 10, 15, 20, 25, 30,35, 40, 45, or 50.

In one embodiment, provided herein is a compound selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof.

In yet another embodiment, provided herein is a compound selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof.

In yet another embodiment, provided herein is a compound selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof.

In yet another embodiment, provided herein is a compound selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof.

In yet another embodiment, provided herein is a compound selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof.

In yet another embodiment, provided herein is a compound selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof.

In yet another embodiment, provided herein is a compound selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compound provided herein contains an alkenyl or alkenylene group,the compound may exist as one or mixture of geometric cis/trans (or Z/E)isomers. Where structural isomers are interconvertible, the compound mayexist as a single tautomer or a mixture of tautomers. This can take theform of proton tautomerism in the compound that contains, for example,an imino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

For example, the compound of Formula II may exist in at least twotautomeric forms as shown below:

Methods of Synthesis

The compounds provided herein can be prepared, isolated, or obtained byany method known to one of skill in the art. In certain embodiments, foran example, a compound of Formula II can be prepared as shown in Scheme1, where L^(s) is a leaving group, e.g., chloro, bromo, iodo, triflate,or tosylate; and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, A, X, Y, and mare each as defined herein.

Compound I-1 is alkylated with compound I-2 to form compound I-3.Compound I-6 is prepared similarly. Subsequently, compound I-3 istreated with compound I-4 to form compound I-5, which is then treatedwith compound I-6 to form a compound of Formula II.

A compound of Formula I can also be prepared as described in U.S. Pat.No. 5,627,027, the disclosure of which is incorporated herein byreference in its entirety.

The starting materials used in the synthesis of the compounds providedherein are either commercially available or can be readily prepared. Forexample, indolenine compounds can be prepared according to the methodsdescribed in U.S. Pat. No. 5,627,027.

Pharmaceutical Compositions

In one embodiment, provided herein is a pharmaceutical compositioncomprising a compound provided herein, e.g., a compound of Formula I, ora tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; and apharmaceutically acceptable excipient.

The pharmaceutical composition that comprises a compound providedherein, e.g., a compound of Formula I, or a tautomer or a mixture of twoor more tautomers thereof; or a pharmaceutically acceptable solvate orhydrate thereof, can be formulated in various dosage forms for oral,parenteral, and topical administration. The pharmaceutical compositioncan also be formulated as modified release dosage forms, includingdelayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-,accelerated-, fast-, targeted-, programmed-release, and gastricretention dosage forms. These dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al.,Eds.; Marcel Dekker, Inc.: New York, N.Y., 2008).

In one embodiment, the pharmaceutical composition is provided in adosage form for oral administration, which comprises a compound providedherein, e.g., a compound of Formula I, or a tautomer or a mixture of twoor more tautomers thereof; or a pharmaceutically acceptable solvate orhydrate thereof.

In another embodiment, the pharmaceutical composition is provided in adosage form for parenteral administration, which comprises a compoundprovided herein, e.g., a compound of Formula I, or a tautomer or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable solvate or hydrate thereof

In yet another embodiment, the pharmaceutical composition is provided ina dosage form for topical administration, which comprises a compoundprovided herein, e.g., a compound of Formula I, or a tautomer or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable solvate or hydrate thereof.

A. Oral Administration

The pharmaceutical composition provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical composition can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical composition provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical composition provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical composition provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical composition provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. The pharmaceuticalcomposition provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serve aplurality of functions, even within the same formulation.

The pharmaceutical composition provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical composition provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical composition provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical composition provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical composition provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical composition provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical composition provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical composition provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical composition intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical composition provided herein is formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical composition for parenteraladministration is provided as ready-to-use sterile solutions. In anotherembodiment, the pharmaceutical composition is provided as sterile drysoluble products, including lyophilized powders and hypodermic tablets,to be reconstituted with a vehicle prior to use. In yet anotherembodiment, the pharmaceutical composition is provided as ready-to-usesterile suspensions. In yet another embodiment, the pharmaceuticalcomposition is provided as sterile dry insoluble products to bereconstituted with a vehicle prior to use. In still another embodiment,the pharmaceutical composition is provided as ready-to-use sterileemulsions.

The pharmaceutical composition provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical composition provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical composition provided herein is dispersedin a solid inner matrix, which is surrounded by an outer polymericmembrane that is insoluble in body fluids but allows the activeingredient in the pharmaceutical composition diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical composition provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical composition provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical composition provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical composition can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical composition provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

The pharmaceutical composition provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcomposition provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid;. Combinations of the variousvehicles can also be used. Rectal and vaginal suppositories may beprepared by compressing or molding. The typical weight of a rectal andvaginal suppository is about 2 to about 3 g.

The pharmaceutical composition provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical composition provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical composition can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical composition canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical composition provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcomposition provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical composition provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical composition provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical composition provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical composition in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,958,458; 5,972,891; 5,980,945; 5,993,855; 6,045,830;6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981;6,270,798; 6,375,987; 6,376,461; 6,419,961; 6,589,548; 6,613,358;6,623,756; 6,699,500; 6,793,936; 6,827,947; 6,902,742; 6,958,161;7,255,876; 7,416,738; 7,427,414; 7,485,322; Bussemer et al., Crit. Rev.Ther. Drug Carrier Syst. 2001, 18, 433-458; Modified-Release DrugDelivery Technology, 2nd ed.; Rathbone et al., Eds.; Marcel Dekker AG:2005; Maroni et al., Expert. Opin. Drug Deliv. 2005, 2, 855-871; Shi etal., Expert Opin. Drug Deliv. 2005, 2, 1039-1058; Polymers in DrugDelivery; Ijeoma et al., Eds.; CRC Press LLC: Boca Raton, Fla., 2006;Badawy et al., J. Pharm. Sci. 2007, 9, 948-959; Modified-Release DrugDelivery Technology, supra; Conway, Recent Pat. Drug Deliv. Formul.2008, 2, 1-8; Gazzaniga et al., Eur. J. Pharm. Biopharm. 2008, 68,11-18; Nagarwal et al., Curr. Drug Deliv. 2008, 5, 282-289; Gallardo etal., Pharm. Dev. Technol. 2008, 13, 413-423; Chrzanowski, AAPSPharmSciTech. 2008, 9, 635-638; Chrzanowski, AAPS PharmSciTech. 2008, 9,639-645; Kalantzi et al., Recent Pat. Drug Deliv. Formul. 2009, 3,49-63; Saigal et al., Recent Pat. Drug Deliv. Formul. 2009, 3, 64-70;and Roy et al., J. Control Release 2009, 134, 74-80.

1. Matrix Controlled Release Devices

The pharmaceutical composition provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art. See, Takada et al. in Encyclopedia ofControlled Drug Delivery; Mathiowitz Ed.; Wiley: 1999; Vol 2.

In certain embodiments, the pharmaceutical composition provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUIDRAGIT®, Rohm America, Inc.,Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical composition provided hereinis formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the pharmaceutical composition.

The pharmaceutical composition provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical composition provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical composition in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art.See, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; and Verma et al.,J. Controlled Release 2002, 79, 7-27.

In certain embodiments, the pharmaceutical composition provided hereinis formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and International Pat. Appl.Publ. No. WO 2002/17918. The AMT controlled-release dosage forms can beprepared according to conventional methods and techniques known to thoseskilled in the art, including direct compression, dry granulation, wetgranulation, and a dip-coating method.

In certain embodiments, the pharmaceutical composition provided hereinis formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical composition provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet-and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Ghebre-SellassieEd.; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology;Ghebre-Sellassie Ed.; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical composition to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical composition provided herein can also be formulated tobe targeted to a particular tissue, receptor, or other area of the bodyof the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 5,709,874;5,759,542; 5,840,674; 5,900,252; 5,972,366; 5,985,307; 6,004,534;6,039,975; 6,048,736; 6,060,082; 6,071,495; 6,120,751; 6,131,570;6,139,865; 6,253,872; 6,271,359; 6,274,552; 6,316,652; and 7,169,410.

Methods of Use

In one embodiment, provided herein is a method of labeling abiomolecule, comprising the step of contacting the biomolecule with acompound disclosed herein, e.g., a compound of Formula I, or a tautomeror a mixture of two or more tautomers thereof; or a pharmaceuticallyacceptable solvate or hydrate thereof

The biomolecule thus labeled is suitable for biological imaging andclinical diagnosis.

In one embodiment, the contacting step is performed at a pH ranging fromabout 5 to about 9 or from about 6 to about 8. In another embodiment,the contacting step is performed at a pH of about 6, about 6.2, about6.4, about 6.6, about 6.8, about 7, about 7.2, about 7.4, about 7.6,about 7.8, or about 8.

In one embodiment, the contacting step is performed at a temperatureranging from about 0 to about 50° C., from about 10 to about 40° C.,from about 20 to 40° C., or from about 30 to about 40° C. In anotherembodiment, the contacting step is performed at a temperature rangingfrom about 35 to about 40° C.

In one embodiment, the contacting step is performed at an aqueoussolution.

In one embodiment, the contacting step is performed under physiologicalconditions.

In one embodiment, the biomolecule is an amino acid based compound. Inanother embodiment, the biomolecule is a protein. In another embodiment,the biomolecule is an antibody. In another embodiment, the biomoleculeis an antibody drug conjugate. In yet another embodiment, thebiomolecule is an antigen. In still another embodiment, the biomoleculeis a polypeptide.

The amino acid based comound can be attached to the compositionsdisclosed herein via the amine, amino, carboxylic acid, or sulfhydrylgroup.

The biomolecule thus labeled is suitable for biological imaging, drugdelivery, clinical diagnosis, forensics, in vitro diagnostics, and invivo diagnostics. Non-limiting applications include drug delivery,immunotherapy, imaging contrast medium or agent, flow cytometry, cellsorting, microscopy, in situ hybridization, immune histochemistry,enzyme-linked immunosorbent assays (ELISA), Western blot,immunoprecipitation, microarrays, etc.

In one embodiment, the biomolecule is a nucleic acid based compound. Inanother embodiment, the biomolecule is a polynucleotide. In anotherembodiment, the biomolecule is a deoxyribonucleic acid. In anotherembodiment, the biomolecule is a ribonucleic acid. In anotherembodiment, the biomolecule is a protein nucleic acid. In anotherembodiment, the biomolecule is an aptamer.

The nucleic acid base (e.g. deoxyribonucleic acid, ribonucleic acid,chimeric nucleic acid, etc.) compounds can be attached to thecompositions disclosed herein via the phosphate attached to the 5′carbon on the ribose or any available amine, methyl, or oxide group onthe base. In some embodiments, the PEG may function as a linker to allowthe labeled nucleic acid to be incorporated into a sequence.

The biomolecule thus labeled is suitable for biological imaging,clinical diagnosis, drug delivery, forensics, and in vitro diagnostics.Non-limiting applications inclue amplification (polymerase chainreaction, transcription mediated amplification, strand displacement,loop-mediated isothermal amplification, rolling circle amplification,ligase chain reaction, nucleic acid sequence based amplification,multiple displacement amplification, helicase dependant amplification,ramification amplification, etc.), real time amplification, sequencing(sanger, real-time, ion semiconductor, synthesis, ligation, nanopore,etc.), detection probes, fluorescent in situ hybridization, antisensetechnology, microarrays, etc.

Kits

In one embodiment, provided herein is a kit which, which includes acontainer and a dosage form of a compound provided herein, e.g., acompound of Formula I, or a tautomer or a mixture of two or moretautomers thereof; or a pharmaceutically acceptable solvate or hydratethereof.

The kit provided herein can further include a device that is used toadminister the compound provided herein. Examples of such devicesinclude, but are not limited to, syringes, needle-less injectors dripbags, patches, and inhalers.

The kit provided herein can further include a pharmaceuticallyacceptable vehicle that can be used to administer one or more thecompound provided herein. For example, if the compound provided hereinis provided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the compound can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: aqueous vehicles, including, but notlimited to, Water for Injection USP, Sodium Chloride Injection, Ringer'sInjection, Dextrose Injection, Dextrose and Sodium Chloride Injection,and Lactated Ringer's Injection; water-miscible vehicles, including, butnot limited to, ethyl alcohol, polyethylene glycol, and polypropyleneglycol; and non-aqueous vehicles, including, but not limited to, cornoil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropylmyristate, and benzyl benzoate.

In another embodiment is a kit for diagnostics or research use. Includedin theses kits is a biomolecule labeled with a compound disclosedherein, e.g., a compound of Formula I, or a tautomer or a mixture of twoor more tautomers thereof; or a pharmaceutically acceptable solvate orhydrate thereof.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); Hz(Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min(minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC(thin layer chromatography); HPLC (high pressure liquid chromatography);CD₃OD (deuterated methanol); THF (tetrahydrofuran); CDCl₃ (deuteratedchloroform); DMSO (dimethylsulfoxide); DMSO-d₆ (deuterateddimethylsulfoxide); EtOAc (ethyl acetate); MeOH (methanol); δ (chemicalshifts in ppm); J (coupling constants in Hz); multiplicities: s(singlet); d (doublet) t (triplet); m (multiplet).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions are conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

Example 1 Preparation of a Compound of Formula XVI

A compound of Formula XVI was prepared according to Scheme 1A, whereinR¹, R⁶, R^(X), R^(Y), A and m are each as defined herein.

The following compounds were prepared according to the proceduresdescribed herein and Scheme 4.

Example 2 Preparation of a Compound of Formula XVe

A compound of Formula XVe is prepared according to Scheme 2, wherein R⁶,A, m, and p are each as defined herein.

Example 3 Preparation of a Compound of Formula XVII

A compound of Formula XVII is prepared according to Scheme 3 and theprocedures as described in Example 1, wherein R¹,_(R) ⁶, R^(X), R^(Y),A, and m are each as defined herein.

Example 4 Preparation of a Compound of Formula A

A compound of Formula A was prepared according to Scheme 4, wherein R¹,R⁶, A, and m are each as defined herein.

To a solution of compound 1 (2 mmol) in nitromethane (1.5 mL) was addedcompound 2 (2 mmol), and the reaction mixture was stirred at 80-99° C.for 8 hrs under argon. The reaction solution was cooled and trituratedwith diethyl ether (5 mL). The supernatant was decanted, and the residuewas washed with diethyl ether and dried in vacuo to give compound 3

A solution of compounds 3 (1 mmol) and 4 (1.2 mmol) in a mixture ofacetic acid (6 mL) and acetic anhydride (6 mL) was stirred at 120° C.for 30-40 min under argon. The reaction solution was cooled andconcentrated, and the residue was washed with diethyl ether (3×30 mL) togive intermediate 5, which was used without further purification. For acompound of Formula A in Scheme 4, where m is 1, 2, or 3,N,N′-diphenylformamidine, malondialdehyde bis(phenylimine), orN-(5-(phenylamino)-2,4-pentadienylidene)aniline was used as compound 4,respectively.

For the compound 6 without hydroxyl group, compound 6 (1 mmol) was addedto a solution of 5 (1.2 mmol) in dry pyridine. The reaction was heatedat 110° C. for 30 min under argon, cooled and then concentrated. Theresidue was purified by a RP-C18 column.

For compound 6 containing a hydroxyl group, a solution of compound 6 (1mmol) in acetic anhydride was added to intermediate 5 (1.2 mmol) inpyridine. The reaction mixture was heated at 110° C. for 30 min underargon, cooled and concentrated. The residue was washed with diethylether, dissolved in hydrochloric acid (12mL, water/MeOH (1:1)) andstirred at room temperature overnight. The mixture was neutralized withsaturated NaHCO₃ and concentrated. The residue was partitioned betweenDCM and water, and the organic phase was separated, dried over anhydridesodium sulfate and concentrated to give the crude product which waspurified on a RP-C18 column eluted with acetonitrile in water to affordthe compounds of Formula (A).

The following compounds were prepared according to the proceduresdescribed herein and Scheme 4.

¹H NMR (500 MHz, CD₃OD) δ 8.25 (t, 2H, J=13.5 Hz), 7.25-7.50 (m, 8H),6.60 (t, 1H, J=12.5 Hz), 6.40 (d, 2H, J=12.5 Hz), 4.35 (t, 4H), 3.80 (t,4H), 3.43-3.71 (m, 22H), 3.32 (s, 3H), 3.23 (t, 2H), 1.75(s, 12H), 1.46(s, 9H); MS (m/z): 821.1.

¹H NMR (500 MHz, CD₃OD) δ 8.25 (t, 2H, J=13.5 Hz), 7.26-7.51 (m, 8H),6.62 (t, 1H, J=12.5 Hz), 6.40 (d, 2H, J=13.5 Hz), 4.37 (t, 4H), 3.81 (t,4H), 3.45-3.73 (m, 24H), 3.34 (s, 3H), 1.75 (s, 12H); MS (m/z): 720.9.

¹H NMR (500 MHz, CD₃OD) δ 8.25 (t, 2H, J=13.5 Hz), 7.25-7.51 (m, 8H),6.62 (t, 1H, J=12.5 Hz), 6.41 (m, 2H), 4.33 (m, 4H), 3.82 (t, 4H, J=5.5Hz), 3.52-3.70 (m, 18H), 3.41 (t, 2H), 1.75(s, 12H); MS (m/z): 688.4.

¹H NMR (500 MHz, CD₃OD) δ 7.95 (m, 2H), 7.64 (m, 1H), 7.26-7.50 (m, 8H),6.63 (t, 2H, J=13.5 Hz), 6.32 (m, 2H), 4.35 (m, 4H), 4.11 (t, 2H), 3.82(m, 4H), 3.55-3.65 (m, 16H), 3.36 (m, 2H), 2.01 (s, 3H), 1.78 (s, 12H);MS (m/z): 756.9.

¹H NMR (500 MHz, CD₃OD) δ 8.27 (t, 2H, J=13.5 Hz), 7.28-7.49 (m, 8H),6.70 (t, 1H, J=12.5 Hz), 6.49 (d, 2H, J=12.5 Hz), 4.31 (t, 4H, J=5.5Hz), 3.86 (m, 4H), 3.56-3.74 (m, 24H), 3.31 (s, 3H), 1.75 (s, 12H); MS(m/z): 746.9.

¹H NMR (500 MHz, CD₃OD) δ 8.26 (t, 2H, J=13.5 Hz), 7.25-7.56 (m, 8H),6.69 (t, 1H, J=12.5 Hz), 6.47 (d, 1H, J=12.5 Hz), 6.38 (d, 1H, J=13.5Hz), 4.34 (t, 2H, J=5.5 Hz), 4.23 (d, 2H, J=5.5 Hz), 3.84 (t, 2H, J=5.5Hz), 3.55-3.74 (m, 15H), 2.8 (m, 1H), 1.75 (s, 12H); MS (m/z): 583.8.

¹H NMR (500 MHz, CD₃OD) δ 8.25 (t, 2H, J=13.5 Hz), 7.29-7.51 (m, 8H),6.65 (t, 1H, J=12.5 Hz), 6.34 (m, 2H), 4.30 (m, 4H), 4.26 (d, 2H, J=5.5Hz), 3.87 (t, 4H, J=5.5 Hz), 3.68-3.55 (m, 19H), 3.46 (t, 2H, J=5.5 Hz),2.88 (t, 1H, J=5.5 Hz), 1.75 (s, 12H); MS (m/z): 701.4.

¹H NMR (500 MHz, CD₃OD) δ 8.26 (t, 2H, J=13.5 Hz), 7.23-7.50 (m, 8H),6.60 (t, 1H, J=12.5 Hz), 6.42 (d, 2H, J=13.5 Hz), 4.30 (t, 4H, J=5.5Hz), 4.26 (d, 4H), 3.85 (t, 4H, J=5.5 Hz), 3.55-3.70 (m, 24H), 2.80 (t,2H, J=5.5 Hz), 1.75 (s, 12H); MS (m/z): 782.4.

¹H NMR (500 MHz, CD₃OD) δ 8.24 (t, 2H, J=13.5 Hz), 7.28-7.50 (m, 8H),6.60 (t, 1H, J=12.5 Hz), 6.44 (d, 2H, J=13.5 Hz), 4.32 (t, 4H), 4.25 (d,2H), 3.89 (t, 4H), 3.50-3.75 (m, 62H), 3.31 (s, 3H), 2.82 (t, 1H), 1.75(s, 12H); MS (m/z): 1156.4.

¹H NMR (500 MHz, CD₃OD) δ 8.26 (t, 2H, J=13.5 Hz), 7.28-7.56 (m, 8H),6.61 (t, 1H, J=12.5 Hz), 6.32 (m, 2H), 4.33 (m, 4H), 3.84 (m, 4H),3.45-3.70 (m, 20H), 3.32 (s, 3H), 1.75 (s, 12H); MS (m/z): 677.8.

¹H NMR (500 MHz, CD₃OD) δ 8.41 (t, 2H, J=13.5 Hz), 7.18-7.41 (m, 8H),6.37 (t, 1H, J=12.5 Hz), 6.34 (d, 2H, J=15.0 Hz), 4.25 (t, 2H, J=5.5Hz), 4.12 (t, 2H, J=5.5 Hz), 3.80 (m, 2H), 3.47 (m, 2H), 3.43-3.57 (m,9H), 3.17 (s, 2H), 1.90 (m, 2H), 1.60 (s, 12H); MS (m/z): 588.3.

^(l)EINMIR (500 MHz, CD₃OD) δ 8.44 (t, 1H, J=13.5 Hz), 8.12 (m, 1H),7.18-7.41 (m, 9H), 6.41 (m, 1H, J=12.5 Hz), 6.38 (d, 1H, J=13.5 Hz),4.25 (t, 2H, J=5.5 Hz), 3.80 (t, 2H, J=5.5 Hz), 3.35-3.55 (m, 10H), 3.21(s, 3H), 1.65 (s, 9H), 1.60 (s, 3H); MS (m/z): 544.3.

¹H NMR (500 MHz, CD₃OD) δ 8.25 (t, 2H, J=13.5 Hz), 7.25-7.50 (m, 8H),6.63 (t, 1H, J=12.5 Hz), 6.38 (d, 1H, J=12.5 Hz), 6.25 (d, 1H, J=13.5Hz), 4.25 (t, 2H, J=5.5 Hz), 3.70 (t, 2H, J=5.5 Hz), 3.65 (s, 3H), 2.01(m, 2H), 1.75 (s, 12H); MS (m/z): 427.5.

¹H NMR (500 MHz, CD₃OD) δ 8.27 (t, 2H, J=13.5 Hz), 7.29-7.54 (m, 8H),6.60 (t, 1H, J=12.5 Hz), 6.35 (d, 1H, J=12.5 Hz), 6.30 (d, 1H, J=15 Hz),4.30 (t, 2H, J=5.5 Hz), 4.22 (t, 2H, J=5.5 Hz), 3.85 (t, 2H, J=5.5 Hz),3.70 (m, 2H), 3.42-3.60 (m, 12H), 3.31 (s, 3H), 2.01 (m, 2H), 1.75 (s,12H); MS (m/z): 603.4.

¹H NMR (500 MHz, CD₃OD) δ 8.26 (t, 2H, J=13.5 Hz), 7.24-7.49 (m, 8H),6.58 (t, 1H, J=12.5 Hz), 6.39 (d, 1H, J=12.5 Hz), 6.28 (d, 1H, J=13.5Hz), 4.35 (t, 2H, J=5.5 Hz), 3.85 (t, 2H, J=5.5 Hz), 3.60-3.75 (m, 9H),3.50 (m, 2H), 1.75 (s, 12H); MS (m/z): 501.6.

¹H NMR (500 MHz, CD₃OD) δ 8.25 (t, 2H, J=13.5 Hz), 7.28-7.52 (m, 8H),6.60 (t, 1H, J=12.5 Hz), 6.41 (d, 2H, J=13.5 Hz), 4.30 (m, 4H), 3.85 (m,4H), 3.52-3.70 (m, 18H), 3.31 (s, 3H), 2.40 (t, 1H), 1.75 (s, 12H); MS(m/z): 705.9.

¹H NMR (500 MHz, CD₃OD) δ 8.26 (t, 2H, J=13.5 Hz), 7.30-7.55 (m, 8H),6.55 (t, 1H, J=12.5 Hz), 6.48 (d, 2H, J=12.5 Hz), 4.34 (t, 4H), 3.75 (t,2H), 3.56-3.65 (m, 48H), 3.32 (s, 3H), 2.40 (t, 2H), 1.75 (s, 12H); MS(m/z): 1058.3.

¹H NMR (500 MHz, CD₃OD) δ 8.24 (t, 2H, J=13.5 Hz), 7.27-7.50 (m, 8H),6.70 (t, 1H, J=12.5 Hz), 6.38 (t, 2H, J=13.5 Hz), 4.32 (m, 4H), 3.80 (m,4H), 3.75 (t, 2H, J=5.5 Hz), 3.58-3.70 (m, 16H), 3.35 (s, 4H), 3.31 (t,2H, J=5.5 Hz), 1.75 (s, 12H); MS (m/z): 802.9.

¹H NMR (500 MHz, CD₃OD) δ 8.17 (t, 2H, J=13.5 Hz), 7.18-7.33 (m, 8H),6.82 (t, 1H, J=12.5 Hz), 6.55 (t, 1H, J=10 Hz), 6.50 (t, 1H, J=13.5 Hz),4.31 (t, 4H, J=5.5 Hz), 3.90 (t, 4H, J=5.5 Hz), 3.51-3.72 (m, 29H), 2.84(t, 2H, J=7.5 Hz), 2.76 (m, 4H), 1.72 (s, 12H). MS (m/z): 891.2.

¹H NMR (500 MHz, CD₃OD) δ 8.23 (t, 2H, J=13.5 Hz),7.24-7.47 (m, 8H),6.59 (t, 1H, J=12.5 Hz), 6.48 (d, 1H, J=12.5 Hz), 6.38 (d, 1H, J=13.5Hz), 4.31 (t, 2H, J=5.5 Hz), 3.87 (t, 2H, J=5.5 Hz), 3.67 (t, 2H, J=5.0Hz), 3.48-3.64 (m, 31H), 2.41 (t, 2H, J=7.5 Hz), 1.72 (s, 12H); MS(m/z): 792.3.

¹H NMR (500 MHz, CD₃OD): δ 8.24 (t, 2H, J=13.5 Hz),7.25-7.47 (m, 8H),6.58 (t, 1H, J=12.5 Hz), 6.48 (d, 1H, J=12.5 Hz), 6.38 (d, 1H, J=13.5Hz), 4.32 (t, 2H, J=5.5 Hz), 3.88 (t, 2H, J=5.5 Hz), 3.68 (m, 2H),3.48-3.65 (m, 31H), 2.41 (m, 2H), 1.72 (s, 12H); MS (m/z): 793.4.

¹H NMR (500 MHz, CD₃OD) δ 8.27 (t, 2H, J=13.5 Hz), 7.47 (d, 2H, J=8.0Hz), 7.39 (m, 2H), 7.32 (m, 2H), 7.24 (m, 2H), 6.57 (t, 1H, J=13.5 Hz),6.32 (d, 2H, J=15.0 Hz), 4.31 (m, 3H), 3.87 (m, 4H), 3.51-3.73 (m, 22H),3.06 (m, 3H), 1.75 (m, 12H); MS (m/z): 705.6.

¹EINMIR (500 MHz, CD₃OD): δ 8.65 (t, 1H, J=13.5 Hz), 7.57 (d, 2H, J=8.0Hz), 7.46 (m, 4H), 7.34 (m, 2H), 6.54 (d, 2H, J=13.5 Hz), 4.40 (m, 3H),3.95 (m, 4H), 3.51-3.70 (m, 29H), 3.31 (s, 3H), 1.80 (m, 12H); MS (m/z):765.8.

¹H NMR (500 MHz, CD₃OD) δ 7.92 (d, 2H, J=12.5 Hz), 7.57 (m, 2H), 7.45(m, 3H), 7.36 (m, 2H), 7.29 (m, 2H), 7.22 (m, 2H), 6.55 (m, 2H), 4.28(m, 3H), 3.86 (m, 4H), 3.42-3.61 (m, 29H), 3.32 (s, 3H), 1.68 (m, 12H);MS (m/z): 816.6.

¹H NMR (500 MHz, CD₃OD) δ 8.14 (t, 2H, J=13.5 Hz),7.16-7.38 (m, 8H),6.50 (t, 1H, J=12.5 Hz), 6.32 (d, 1H, J=15 Hz), 6.27 (d, 1H, J=13.5 Hz),4.23 (t, 4H, J=5.5 Hz), 3.79 (t, 4H, J=5.5 Hz), 3.39-3.79 (m, 24H), 3.25(m, 2H), 2.34 (m, 2H), 1.63 (s, 12H); MS (m/z): 805.5.

¹H NMR (500 MHz, CD₃OD) δ 8.05 (t, 2H, J=13.5 Hz),7.09-7.32 (m, 8H),6.44 (t, 1H, J=12.5 Hz), 6.25 (d, 1H, J=13.5 Hz), 6.22 (d, 1H, J=13.5Hz), 4.16 (t, 4H, J=6.5 Hz), 3.73 (t, 4H, J=5.5 Hz), 3.34-3.54 (m, 28H),2.36 (m, 4H), 1.57 (s, 12H); MS (m/z): 852.7.

¹H NMR (500 MHz, CD₃OD) δ 8.23 (t, 2H, J=13.5 Hz), 7.46 (d, 2H, J=8.0Hz), 7.36 (t, 2H, J=8.0 Hz), 7.26 (d, 2H, J=8.0 Hz), 7.23 (t, 2H, J=7.5Hz), 6.60 (t, 1H, J=13.5 Hz), 6.38 (m, 2H),4.30 (t, 4H, J=5.5 Hz), 3.88(t, 4H, J=5.5 Hz), 3.51-3.58 (m, 24H), 1.72 (s, 12H); MS (m/z): 757.2.

¹H NMR (500 MHz, CD₃OD) δ 8.23 (t, 2H, J=13.5 Hz),7.18-7.32 (m, 8H),6.83 (t, 1H, J=12.5 Hz), 6.50 (t, 1H, J=12.5 Hz), 6.48 (d, 1H, J=13.5Hz), 4.33 (t, 4H, J=5.5 Hz), 3.90 (t, 4H, J=5.5 Hz), 3.84 (m, 4H),3.34-3.54 (m, 24H), 2.81 (m, 8H), 2.62 (m, 4H), 1.72 (s, 12H); MS (m/z):1046.2.

Example 5 Preparation of a Compound of Formula XVIII

A compound of Formula XVIII was prepared according to Scheme 5, whereinR¹, R⁶, R^(4a), R^(9a), A, and m are each as defined herein.

To a solution of 1 (16.7 mmol) in dimethylformamide (35 mL) were addedCs₂CO₃ (18.4 mmol) and 2 (16.7 mmol) and the reaction mixture wasstirred at 60° C. for 16 hrs. The reaction solution was cooled andconcentrated, and the residue was purified by column chromatography withEtOAc/DCM to give 3.

Compounds 3a and 3b were prepared according to the procedures describedherein and Scheme 5.

¹H NMR (500 MHz, CD₃OD) δ 7.42 (d, 1H, J=8.5 Hz), 6.84 (m, 2H), 4.14 (m,2H), 3.85 (m, 2H), 3.62-3.75 (m, 10H), 3.54 (m, 2H), 3.37 (s, 3H), 2.27(s, 3H), 1.28 (s, 6H); MS (m/z): 366.5

¹H NMR (500 MHz, CD₃OD) δ 7.47 (d, 1H, J=8.5 Hz), 6.87 (m, 1H), 6.82 (m,1H), 4.18 (m, 2H), 4.14 (m, 2H), 3.86 (m, 2H), 3.73 (m, 2H), 3.65-3.70(m, 10H), 2.42 (m, 1H), 2.27 (s, 3H), 1.28 (s, 6H); MS (m/z): 390.6.

A mixture of compounds 3 (2.7 mmol) and 4 (2.7 mmol) was stirred at80-99° C. for 8 hrs under argon.The reaction solution was cooled andconcentrated, and the residue was washed with diethyl ether to give 5.

Compounds 5a and 5b were prepared according to the procedures describedherein and Scheme 5.

¹1-1NMIR (500 MHz, CD₃OD): δ 7.73 (d, 1H, J=8.5 Hz), 7.35 (m, 1H), 7.17(m, 1H), 4.20 (m, 2H), 3.97 (m, 3H), 3.85 (m, 2H), 3.50-3.68 (m, 12H),3.34 (s, 3H), 2.13 (s, 3H), 1.54 (s, 6H); MS (m/z): 380.3.

^(I)E NMR (500 MHz, CD₃OD) δ 7.74 (m, 1H), 7.37 (m, 1H), 7.20 (m, 1H),4.25 (m, 2H), 4.18 (m, 2H), 3.90 (m, 2H), 3.72 (m, 2H), 3.61-3.67 (m,10H), 3.32 (s, 3H), 2.85 (m, 1H), 2.18 (s, 3H), 1.59 (s, 6H); MS (m/z):404.6.

A solution of compounds 5 (2.7 mmol) and 6 (2.7 mmol) in a mixture ofacetic acid (3 mL) and acetic anhydride (3 mL) was stirred at 110° C.for 30-40 mins under argon. The reaction mixture was cooled andconcentrated, and the residue was washed with diethyl ether (3×10 mL) togive intermediate compound 7, which was used for the following reactionwithout further purification. For the compounds of Formula XVIII inScheme 5,where m is 1, 2, or 3, N,N′-diphenylformamidine,malondialdehyde bis(phenylimine), orN-(5-(phenylamino)-2,4-pentadienylidene)aniline was used as compound 6,respectively.

To a solution of 8 (0.6 mmol) in dry pyridine (5 mL) was added 7 (0.6mmol) and the reaction mixture was stirred at 110° C. for 40 mins underargon. The reaction solution was cooled and concentrated, and theresidue was washed with diethyl ether, and dried in vacuo. The residuewas re-dissolved in DCM, washed with hydrochloric acid (0.1 M), brineand concentrated. The crude product was purified on a RP-C18 columneluted with acetonitrile in water to afford the compounds of formulaXVIII.

The following compounds were prepared according to the proceduresdescribed herein and Scheme 5.

¹H NMR (500 MHz, CD₃OD) δ 8.09 (t, 2H, J=13.5 Hz), 7.16 (m, 2H), 7.10(m, 2H), 6.95 (m, 2H), 6.51 (t, 1H, J=12.5 Hz), 6.13 (d, 2H, J=15.0 Hz),4.56 (m, 4H), 4.13 (m, 6H), 3.82 (m, 4H), 3.49-3.68 (m, 23H), 3.27 (m,6H), 2.81 (m, 1H), 1.75 (m, 12H); MS (m/z): 820.2.

¹H NMR (500 MHz, CD₃OD) δ 8.11 (t, 2H, J=10 Hz), 7.21 (m, 2H), 7.10 (m,2H), 6.94 (m, 2H), 6.52 (t, 1H, J=10 Hz), 6.16-6.28 (m, 2H), 4.60 (m,4H), 4.25 (m, 2H), 4.13 (m, 6H), 3.82 (m, 6H), 3.47-3.68 (m, 35H), 3.27(m, 6H), 2.82 (m, 1H), 1.67 (m, 12H); MS (m/z): 996.3.

¹1-1 NMR (500 MHz, CD₃OD) δ8.11 (t, 2H, J=13.5 Hz), 7.21 (m, 2H), 7.10(m, 2H), 6.94 (m, 2H), 6.52 (t, 1H, J=12.5 Hz), 6.16-6.28 (m, 2H), 4.60(m, 4H), 4.25 (m, 2H), 4.13 (m, 6H), 3.82 (m, 6H), 3.47-3.68 (m, 35H),3.27 (m, 6H), 2.82 (m, 1H), 1.67 (m, 12H); MS (m/z): 996.3.

¹H NMR (500 MHz, CD₃OD) δ 8.08 (t, 2H, J=13.5 Hz), 7.13 (d, 2H, J=8.5Hz), 7.10 (m, 2H), 6.96 (m, 2H), 6.48 (m, 1H), 6.15 (d, 2H, J=15.0 Hz),4.19 (m, 4H), 3.87 (m, 4H), 3.64-3.72 (m, 29H), 3.45 (m, 2H), 3.35 (m,6H), 1.75 (m, 12H); MS (m/z): 850.6.

¹H NMR (500 MHz, CD₃OD) δ 8.10 (t, 2H, J=14.0 Hz), 7.15 (d, 2H, J=9.0Hz), 7.09 (m, 2H), 6.94 (m, 2H), 6.48 (t, 1H, J=12.5 Hz), 6.26 (d, 2H,J=14.0 Hz), 4.59 (m, 7H), 4.24 (m, 2H), 4.14 (m, 3H), 3.83 (m, 6H),3.47-3.68 (m, 59H), 1.66 (m, 12H); MS (m/z): 1203.1.

¹H NMR (500 MHz, CD₃OD) δ 8.12 (t, 2H, J=13.5 Hz), 7.18 (d, 2H, J=8.0Hz), 7.12 (m, 2H), 6.97 (m, 2H), 6.53 (t, 1H, J=15.0 Hz), 6.17 (d, 2H),4.59 (m, 1H), 4.15 (m, 4H), 3.84 (m, 4H), 3.49-3.72 (m, 36H), 3.35 (m,3H), 2.43 (m, 1H), 1.69 (m, 12H), 1.42 (s, 9H); MS (m/z): 954.5.

¹H NMR (500 MHz, CD₃OD) δ 8.47 (t, 1H, J=13.5 Hz), 7.24 (d, 2H, J=9.0Hz), 7.17 (m, 2H), 6.95 (m, 2H), 6.25 (d, 1H, J=13.5 Hz), 4.16 (m, 2H),3.85 (m, 4H), 3.61-3.70 (m, 32H), 3.51 (m, 2H), 3.32 (s, 3H), 2.82 (m,1H), 1.73 (m, 12H); MS (m/z): 794.3.

¹H NMR (500 MHz, CD₃OD) δ 8.45 (t, 1H, J=13.5 Hz), 7.26 (d, 2H, J=8.5Hz), 7.19 (m, 2H), 7.03 (m, 2H), 6.31 (d, 2H, J=15.0 Hz), 4.19 (m, 4H),3.87 (m, 4H), 3.73 (m, 4H), 3.64-3.68 (m, 28H), 3.53 (m, 2H), 3.35 (s,3H), 1.69 (m, 12H); MS (m/z): 824.6.

Example 6 Preparation of a Compound of Formula XVIf

A compound of Formula XVIf is prepared according to Scheme 6, whereinR⁶, A, Z, m, and p are each as defined herein.

To a solution of compound 1 (0.2 mmol) in DCM (2 mL) was addedtriethylamine (0.3 mmol) and compound 2 (0.3 mmol) consequentially andthe solution stirred at room temperature for 40 min. The reactionmixture was diluted by DCM, washed with hydrochloric acid (0.1 M), brineand concentrated. The residue was purified on a RP-C18 column elutedwith acetonitrile in water to afford the target compounds.

Compound 1 is prepared according to Scheme 4, wherein R¹, R⁶, R^(X),R^(Y), and m are each as defined herein.

The following compounds were prepared according to the proceduresdescribed herein and Scheme 6.

¹H NMR (500 MHz, CD₃OD) δ 8.25 (t, 2H, J=13.5 Hz), 7.47 (d, 2H, J=8.5Hz), 7.39 (m, 2H), 7.32 (m, 2H), 7.24 (m, 2H), 6.77 (s, 2H), 6.57 (t,1H, J=13.5 Hz), 6.38 (d, 2H, J=15.0 Hz), 4.31 (m, 3H), 3.88 (m, 4H),3.73 (m, 2H), 3.45-3.55 (m, 26H), 3.24 (m, 2H), 2.42 (m, 2H), 1.72 (m,12H); MS (m/z): 872.6.

¹H NMR (500 MHz, CD₃OD) δ 8.23 (t, 2H, J=12.5 Hz), 7.47 (d, 2H, J=9.0Hz), 7.38 (m, 2H), 7.33 (m, 2H), 7.24 (m, 2H), 6.57 (t, 1H, J=12.5 Hz),6.38 (m, 2H), 4.46 (m, 1H), 4.31 (m, 5H), 3.87 (m, 4H), 3.43-3.58 (m,26H), 3.15 (m, 2H), 2.86 (m, 1H), 2.72 (m, 1H), 2.17 (m, 2H), 1.72 (m,12H), 1.55-1.61 (m, 4H), 1.38-1.41 (m, 2H); MS (m/z): 947.8.

Example 7 Preparation of a Compound of Formula XVIg

A compound of Formula XVIg is prepared according to Scheme 7, whereinR⁶, A, m, P, and Z are each as defined herein.

Compound 1 (0.1 mmol), EDCI (0.15 mmol), HOBt (0.15 mmol), amines withfunctional group (0.15 mmol) (such as amine, hydroxyl, DABCO, maleimide)were dissolved in DCM (10.0 mL). The reaction mixture was stirred atroom temperature overnight and then concentared. The residue waspurified on a RP-C18 column eluted with acetonitrile in water to affordthe target compounds.

Compound 1 is prepared according to Scheme 4, wherein R¹, R⁶, R^(X),R^(Y), and m are each as defined herein.

The following compounds were prepared according to the proceduresdescribed herein and Scheme 7.

¹H NMR (500 MHz, CD₃OD) δ 8.15 (t, 2H, J=13.5 Hz), 7.14-7.36 (m, 8H),6.46 (t, 1H, J=12.5 Hz), 6.28 (d, 1H, J=13.5 Hz), 6.21 (d, 1H, J=13.5Hz), 4.19 (t, 4H, J=5.5 Hz), 3.75 (t, 4H, J=5.5 Hz), 3.38-3.60 (m, 26H),3.21 (m, 2H), 2.80 (m, 2H), 2.30 (m, 2H), 1.74 (m, 2H), 1.63 (s, 12H);MS (m/z): 861.7.

¹H NMR (500 MHz, CD₃OD): δ 8.09 (t, 2H, J=13.5 Hz), 7.07-7.47 (m, 8H),6.44 (t, 1H, J=12.5 Hz), 6.24 (d, 1H, J=13.5 Hz), 6.20 (d, 1H, J=12.5Hz), 4.16 (t, 4H, J=6.0 Hz), 3.72 (t, 2H, J=5.5 Hz), 3.15-3.56 (m, 34H),3.30 (m, 1H), 2.22 (m, 2H), 1.77 (m, 4H), 1.57 (s, 12H), 1.11-1.25 (m,4H); MS (m/z): 891.9.

¹H NMR (500 MHz, CD₃OD) δ 8.14 (t, 2H, J=13.5 Hz),7.16-7.38 (m, 8H),6.77 (s, 2H), 6.50 (t, 1H, J=12.5 Hz), 6.32 (d, 1H, J=15 Hz), 6.27 (d,1H, J=13.5 Hz), 4.23 (t, 4H, J=6.0 Hz), 3.79 (t, 4H, J=6.0 Hz),3.39-3.79 (m, 28H), 3.25 (t, 2H, J=7.5 Hz), 2.34 (t, 2H, J=7.5 Hz), 1.63(s, 12H); MS (m/z): 927.7.

¹H NMR (500 MHz, CD₃OD) δ 8.14 (t, 2H, J=13.5 Hz), 7.11-7.52 (m, 16H),6.48 (t, 1H, J=12.5 Hz), 6.26 (d, 1H, J=13.5 Hz), 6.23 (d, 1H, J=13.5Hz), 4.50 (s, 2H), 4.18 (t, 4H, J=6.0 Hz), 3.75 (t, 4H, J=6.0 Hz),3.21-3.52 (m, 31H), 2.37 (t, 2H, J=7.5 Hz), 2.13 (t, 2H, J=7.5 Hz), 1.59(s, 12H); MS (m/z): 1052.5.

¹H NMR (500 MHz, CD₃OD) δ 8.12 (t, 2H, J=13.5 Hz), 7.12-7.36 (m, 8H),6.48 (t, 1H, J=12.5 Hz), 6.28 (d, 1H, J=12.5 Hz), 6.25 (d, 1H, J=13.5Hz), 4.51 (m, 1H), 4.20 (m, 5H), 3.76 (t, 4H, J=6.0 Hz), 3.07-3.60 (m,45H), 2.80 (m,1H), 2.77 (m, 1H), 2.55 (m, 1H), 2.31(t, 2H, J=10.0 Hz),2.08(t, 2H, J=10.0 Hz), 1.61 (m, 12H), 1.53 (m, 4H), 1.43 (m, 2H); MS(m/z): 1150.1.

Example 8 Preparation of a Compound of Formula E

A compound of Formula E was prepared according to Scheme 8, wherein R¹,R⁶, R^(X) and R^(Y) are each as defined herein.

A mixture of 1 and 2 was stirred at 110° C. overnight under argon,cooled and then triturated with diethyl ether (5 mL). The supernatantwas decanted, and the residue was washed with diethyl ether and dried invacuum to yield compound 3.

A solution of compounds 3 (0.6 mmol) and 4 (0.6 mmol) in aceticanhydride (6 mL) was stirred at 110° C. for 30-40 min. The reactionsolution was cooled and concentrated. The residue was washed withdiethyl ether (3×5 mL) to give intermediate 5, which was used for thenext reaction without further purification. For the compounds of FormulaE in Scheme 8, where m is 1, 2, or 3, N,N′-diphenylformamidine,malondialdehyde bis(phenylimine), orN-(5-(phenylamino)-2,4-pentadienylidene)aniline was used as compound 4,respectively.

To a solution of compounds 5 (0.6 mmol) and 6 (0.6 mmol) in ethanol (10mL) was added sodium acetic (1.8 mmol). The reaction was stirred underreflux at 80° C. for 2 h, cooled and concentrated. The residue waswashed with diethyl ether, dissolved in DCM, washed with hydrochloricacid (0.1 M) and brine and concentrated. The residue was was purified ona RP-C18 column eluted with acetonitrile in water to afford the targetcompound E.

The following compounds were prepared according to the proceduresdescribed herein and Scheme 8.

¹H NMR (500 MHz, CD₃OD) δ 7.87 (m, 2H), 7.65 (m, 4H), 7.52 (t, 2H, J=8.5Hz), 7.37 (m, 2H), 6.52 (m, 3H), 4.54 (t, 3H, J=5.5 Hz), 3.92 (t, 3H,J=5.5 Hz), 3.67 (m, 3H), 3.44-3.52 (m, 24H), 2.50 (m, 2H); MS (m/z):729.4.

¹H NMR (500 MHz, CD₃OD) δ 7.90 (m, 2H), 7.76 (m, 2H), 7.61 (m, 3H), 7.52(m, 3H), 7.49 (m, 2H), 6.52 (m, 1H), 4.51 (m, 2H), 3.91 (m, 2H),3.46-3.66 (m, 28H); MS (m/z): 744.5.

Example 9 Preparation of a Compound of Formula F

A compound of Formula F was prepared according to Scheme 9, whereinR^(c) and R^(X) are each as defined herein.

A mixture of compounds 1 and 2 was stirred at 110° C. under argon for 24h, cooled to room temperature and triturated with diethyl ether (5 mL).The supernatant was decanted, and the residue was washed with diethylether and dried in vacuum to give 3.

Compounds 3 (0.4 mmol), 4 (0.2 mmol) and NaOAc (0.6 mmol) weredissvolved in acetic acid (5 mL) and reaction was stirred at 110° C. for1 h under argon. The solution was concentrated, and the residue wasdissolved in DCM, washed by hydrochloric acid (0.1 M) and brine and thenconcentrated. The residue was purified on a RP-C18 column eluted withacetonitrile in water to afford the target compound F.

The following compounds were prepared according to the proceduresdescribed herein and Scheme 9.

¹H NMR (500 MHz, CD₃OD) δ 8.44 (m, 2H), 7.51 (d, 2H, J=7.5 Hz), 7.42 (t,2 H, J=8.0 Hz), 7.35 (d, 2H, J=8.0 Hz), 7.27 (m, 2H), 6.45 (d, 2H,J=13.5 Hz), 4.37 (m, 3H), 3.90 (m, 4H), 3.55-3.58 (m, 20H), 3.29 (m,8H), 2.73(m, 3H), 1.73 (s, 12H); MS (m/z): 857.6.

Example 10 Preparation of a Compound of Formula G

A compound of Formula G was prepared according to Scheme 10, wherein R¹,R⁶, R^(X), R^(Y), and m are each as defined herein.

A mixture of compounds 1 and 2 was stirred under argon at 110° C. for 24h, cooled and triturated with diethyl ether (5 mL). The supernatant wasdecanted, and the residue was washed with diethyl ether and dried invacuum to yield compound 3.

A solution of compounds 3 (0.4 mmol) and 4 (0.4 mmol) in aceticanhydride (4 mL) was stirred at 110° C. for 40 min under argon. Thereaction solution was cooled and concentrated to give the residue whichwas washed with diethyl ether to give intermediate 5.

Compounds 5 (0.4 mmol) and 6 (0.4 mmol) were dissolved in dry pyridine(4 mL) and the reaction was stirred at 110° C. for 40 min under argon.The solution was concentrated, and the residue was dissolved in DCM,washed by hydrochloric acid (0.1 M) and brine and then concentrated. Theresidue was purified on a RP-C18 column eluted with acetonitrile inwater to afford the target compound G.

The following compounds were prepared according to the proceduresdescribed herein and Scheme 10.

¹H NMR (500 MHz, CD₃OD) δ 7.93-7.96 (m, 3H), 7.81 (d, 1H), 7.61 (m, 1H),7.48 (m, 1H), 7.38 (m, 1H), 7.31 (m, 1H), 7.12-7.16 (m, 2H), 6.78 (d,1H), 6.53 (m, 1H), 6.14 (m, 1H), 4.68 (m, 1H), 4.17 (m, 2H), 3.95 (m,2H), 3.83 (m, 2H), 3.65 (m, 3H), 3.44-3.54 (m, 24H), 1.68 (s, 6H); MS(m/z): 740.0.

¹H NMR (500 MHz, CD₃OD) δ 7.91-7.98 (m, 3H), 7.78 (m, 1H), 7.61 (m, 1H),7.48 (m, 1H), 7.38 (m, 1H), 7.31 (m, 1H), 7.13-7.18 (m, 2H), 6.75 (d,1H), 6.55 (d, 1H), 6.18 (d, 1H), 4.67 (m, 2H), 4.18 (m, 2H), 3.94 (m,2H), 3.83 (m, 2H), 3.65 (m, 3H), 3.47-3.59 (m, 24H), 1.68 (s, 6H); MS(m/z): 736.8.

Example 11 Labeling of a Biomolecule

A labeled biomolecule is prepared according to Scheme 11, wherein R⁶, m,and p are each as defined herein.

Example 12 Labeling of a Biomolecule

A labeled biomolecule is prepared according to Scheme 12.

Example 13 Labeling of a Biomolecule

A labeled biomolecule is prepared according to Scheme 13.

Example 14 Labeling of a Biomolecule

A labeled biomolecule is prepared according to Scheme 14.

Example 15 Photophysical Properties of Select Dyes

The photophysical properties of a variety of cyanine dyes in dimethylsulfoxide has been measured by the DU 800 spectrophotometer. Thespectral results, with respect to the absorption, emission, andextinction coefficients, are summarized in Table below.

No. Excitation (nm) Emission (nm) Extinction Coefficient A2 649 667 1.63× 10⁵ A10 650 691 6.57 × 10⁴ A19 649 667 2.32 × 10⁵ A20 649 667 1.70 ×10⁵ A24 752 785 9.79 × 10⁴ A28 649 667 1.16 × 10⁵ B1 649 699 6.12 × 10⁴B3 672 695  2.2 × 10⁵ B8 565 598 5.95 × 10⁴ C1 649 667 1.02 × 10⁵ D3 649667 6.94 × 10⁴ D4 649 667 6.42 × 10⁴ D5 649 667 9.16 × 10⁴ E1 661 6827.11 × 10⁴ E2 661 682 7.31 × 10⁴ F1 785 817 1.16 × 10⁵ G1 661 685 7.65 ×10⁴ G2 652 671 4.23 × 10⁴

The results in above table show that the length of the cyanine bridge iscorrelated with the wavelength, and for each vinyl addition to thepolymethine chain the wavelength increases by roughly 100 nm. Foreample, excitation of cyanine dyes (n=2) range from 649 nm to 672 nm,while the cyanine dye B8 (n=1) had a less excitation at 565 nm and anemission at 598 nm, and the enhanced excitation and emission of A24(n=3) was found to be 752 nm and 785 nM respectively.

The incorporation of a cyclohexene ring in the center of the polymethinechain results in compound F1 (n=3), with highest absorption of 785 nmand emission of 817 nm. It has been considered that the six-memberedcyclohexene could stabilize the conformation to the molecule and thusenhance the photophysical properties.

The sulfur containing cyanine dyes E1, E2, G1 and G2 affect thewavelength, but to a lesser degree than the chromophore length.

Example 16 Solubility of Select Dyes

The comparative solubility of select cyanine dyes is shown below.

Aqueous Compound solubility

<1 mM

 166.6 mM

<1 mM

 71.4 mM

 62.5 mM

The labeling of cyanine dyes to biomolecules involves covalentconjugations in aqueous buffer solutions under mild conditions. Toimprove the water solubility, PEGylation of the cyanine dyes has beenconsidered to be a viable strategy in many cases.

The results in the above table show that the addition of PEG increasesthe solubility of the dye. For example, The dye I with N-methyl andN′-hydroxysuccinimidyl esters is poorly soluable in water andprecipitating at concentration of 1 mM at room temperature, whileincorporation of N-PEG4-methyl and N′-PEG4-OSu results in the dye A19which shows a significant improvement in water solubility at maximumconcentration of 166.6 mM. Similarly, compared to the non-PEG dye II,N-PEG4-methyl in A14 and N′-PEG-2-alcohol in A15 increase dye solubilitywith maximum concentrations of 71.4 mM and 62.5 mM respectively.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A compound of Formula I:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein: A is ananion bearing a negative charge; L is

wherein: each R^(L) is independently (a) hydrogen, deuterium, azido,cyano, halo, nitro, oxo, sulfo, —OPO₃H₂, or PO₃H₂; (b) C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1d),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); X^(a) is (a) hydrogen,deuterium, azido, cyano, halo, nitro, oxo, sulfo, OPO₃H₂, or —PO₃H²; (b)C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl,C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl , each of which is optionallysubstituted with one or more substituents Q; (c) —C(R^(1a)R^(1b)),—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); (d) —(CH₂CH₂O)_(p)-L¹-Z¹,—(CH₂CH₂O)_(p)—COOH, —(CH₂CH₂O)_(p)—N₃, —(CH₂CH₂O)_(p) —OH,—(CH₂CH₂O)_(p)—alkyne, —(CH₂CH₂O)_(p)-biotin, —(CH₂CH₂O)_(p)-NHS ester,—(CH₂CH₂O)_(p)-amine, —(CH₂CH₂O)_(p)-DBCO, —(CH₂CH₂O)_(p)-Fmoc,—(CH₂CH₂O)_(p)-aldehyde, —(CH₂CH₂O)_(p)-phosphonate,—(CH₂CH₂O)_(p)-tosylate, —(CH₂CH₂O)_(p)-FPF ester, —(CH₂CH₂O)_(p)-Boc,—(CH₂CH₂O)_(p)-aminooxy, —(CH₂CH₂O)_(p)-bromo, —(CH₂CH₂O)_(p)-mal, or-(CH₂CH₂O)_(p)-propargyl; or (e) carboxycylic acid, amine, azide, DBCO,hydrazide, maleimide, NHS ester, TCO, tetrazine, or biotin; m is aninteger of 1, 2, or 3; and n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;X and Y are each independently C(R^(Xa)R^(Xb)), O, S, or NR^(Xc);wherein: R^(Xa) and R^(Xb) are each independently (a) hydrogen ordeuterium; or (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; andR^(Xc) is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl,or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R¹ is (a) hydrogen or deuterium; (b) C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀aralkyl, heteroaryl, or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R¹,—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or (d) —(CH₂CH₂O)_(p)-L¹-Z¹; wherein: L¹ is C₁₋₁₀ alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀alkenylene, C₂₋₁₀ alkynylene, C₃₋₁₅ cycloalkylene, —C₁₋₁₀heteroalkylene—C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀ aralkylene,heteroarylene, or heterocyclylene; Z¹ is (a) amino, azido, chloro,bromo, iodo, or thiol; (b) N-maleimido, N-3,4-dibromo-maleimido, C₂₋₆alkynyl, heterocyclyl containing a carbon-carbon triple, acrylyl,3-sulfo-N-succinimidyloxycarbonyl, tetrafluorophenoxycarbonyl,pentofluorophenoxycarbonyl, C₂₋₆ alkynyloxy, C₃₋₁₅ cycloalkyloxycontaining a carbon-carbon triple, C₆₋₂₀ aryloxy containing acarbon-carbon triple, or heterocyclyloxy containing a carbon-carbontriple; (c) —OP(OR^(1a))(NR^(1b)R^(1c)), ——OP((NR^(1b)R^(1c))₂,—OS(O)₂R^(1a), or —S—SR^(1a); or (d) Z⁶; and p is an integer of 1 to 50;R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, and R¹⁰ are each independently (a) hydrogen,deuterium, azido, cyano, halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b)C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl,C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c), (d) R² and R³, R⁴ and R⁵, R⁷and R⁸, or R⁹ and R¹⁰, each pair together with the carbon atoms to whichthey are attached independently form C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl,heteroaryl, or heterocyclyl; (e) R³ and R⁴, or R⁸ and R⁹, each pairtogether with the carbon atoms to which they are attached independentlyform C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, heteroaryl, or heterocyclyl; or (f)—O(CH₂CH₂O)_(r)-L^(r)-Z^(r), with the proviso that when R^(c) is not—(CH₂CH₂O)_(p)-L¹—Z¹, at least one of R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹,and R¹⁰ is —O(CH₂CH₂O)_(r)—L^(r)-Z^(r); wherein: L^(r) is C₁₋₁₀alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene,C₃₋₁₅ cycloalkylene, C₁₋₁₀ heteroalkylene-C₃₋₁₅ cycloalkylene, C₆₋₂₀arylene, C₇₋₂₀ aralkylene, heteroarylene, or heterocyclylene; Z^(r) is(a) hydrogen, deuterium, halo, cyano, nitro, sulfo, —OPO₃H₂, or —PO₃H₂;(b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀aryl, C₇₋₂₀ aralkyl, heteroaryl, or heterocyclyl; (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or (d) Z¹; and r is aninteger of 1 to 50; R⁶ is (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀aralkyl, heteroaryl, or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)₂NR^(1b)R^(1c); or (d) —(CH₂CH₂O)_(q)-L⁶-Z⁶; wherein: L⁶ is C₁₋₁₀alkylene, C₁₋₁₀ heteroalkylene, C₂₋₁₀ alkenylene, C₂₋₁₀ alkynylene,C₃₋₁₅ cycloalkylene, C₆₋₂₀ arylene, C₇₋₂₀ aralkylene, heteroarylene, orheterocyclylene; Z⁶ is (a) hydrogen, deuterium, halo, cyano, nitro,sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl, orheterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or (d) Z¹; and q is aninteger of 1 to 50; and each R^(1a), R^(1b) R^(1c), and R^(1d) isindependently (a) hydrogen or deuterium; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl,or heterocyclyl; (c) R^(1a) and R^(1c) together with the C and N atomsto which they are attached form heterocyclyl; or (d) R^(1b) and R^(1c)together with the N atom to which they are attached form heteroaryl orheterocyclyl; wherein each alkyl, alkylene, heteroalkylene, alkenyl,alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl,arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl,heterocyclylene, alkynyloxy, cycloalkyloxy, aryloxy, and heterocyclyloxyis optionally substituted with one or more substituents Q, where each Qis independently selected from (a) deuterium, azido, cyano, halo, nitro,oxo, sulfo, —OPO₃H₂, and —PO₃H₂; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); wherein each Q^(a) is independently selected from the groupconsisting of (a) deuterium, azido, cyano, halo, nitro, oxo, sulfo,—OPO₃H₂, and —PO₃H₂; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and(c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g),—OR^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g),—OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g),—OS(O)₂NR^(f)R^(g), NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heteroaryl or heterocyclyl.
 2. The compound ofclaim 1, having the structure of Formula II:

or a tautomer or a mixture of two or more tautomers thereof or apharmaceutically acceptable solvate or hydrate thereof.
 3. The compoundof claim 1, having the structure of Formula III:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein: R^(X)and R^(Y) are each independently (a) hydrogen, deuterium, azido, cyano,halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂;(b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 4. The compound of claim 1,having the structure of Formula IV:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein: R^(X)and R^(Y) are each independently (a) hydrogen, deuterium, azido, cyano,halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 5. The compound of claim 1,having the structure of Formula V:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof.
 6. The compoundof claim 1, having the structure of Formula IX:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof.
 7. The compoundof claim 1, having the structure of Formula XII:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof.
 8. The compoundof claim 1, selected from:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein: R^(X)and R^(Y) are each independently (a) hydrogen, deuterium, azido, cyano,halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 9. The compound of claim 1,selected from:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein: R^(X)and R^(Y) are each independently (a) hydrogen, deuterium, azido, cyano,halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and wherein: Z is (a)hydrogen, deuterium, halo, O, S, N, or Se; (b) Z¹ or Z⁶; or (c)R^(Xc)Z¹, R^(Xa)R^(Xc)Z¹, R^(Xc)Z⁶, R^(Xa)R^(Xc)Z⁶, C(R^(Xa)R^(Xb)), orNR^(Xc).
 10. The compound of claim 1, selected from:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein: R^(X)and R^(Y) are each independently (a) hydrogen, deuterium, azido, cyano,halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and wherein: Z is (a)hydrogen, deuterium, halo, O, S, N, or Se; (b) Z¹ or Z⁶; or (c)R^(Xc)Z¹, R^(Xa)R^(Xc)Z¹, R^(Xc)Z⁶, R^(Xa)R^(Xc)Z⁶, C(R^(Xa)R^(Xb)), orNR^(Xc).
 11. The compound of claim 1, selected from:

or a tautomer or a mixture of two or more tautomers thereof; or apharmaceutically acceptable solvate or hydrate thereof; wherein: R^(X)and R^(Y) are each independently (a) hydrogen, deuterium, azido, cyano,halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q; or (c) —C(O)R^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a)—OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and wherein: Z is (a)hydrogen, deuterium, halo, O, S, N, or Se; (b) Z¹ or Z⁶; or (c)R^(Xc)Z¹, R^(Xa)R^(Xc)Z¹, R^(Xc)Z⁶, R^(Xa)R^(Xc)Z⁶, C(R^(Xa)R^(Xb)), orNR^(Xc).
 12. The compound of claim 1, selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof.
 13. Thecompound of claim 1, selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof.
 14. Thecompound of claim 1, selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof; wherein: Z is(a) hydrogen, deuterium, halo, O, S, N, or Se; (b) Z¹or Z⁶; or (c)R^(Xc)Z¹, R^(Xa)R^(Xc), Z¹, R^(Xc)Z⁶, R^(Xa)R^(Xc)Z⁶, C(R^(Xa)R^(Xb)),or NR^(Xc).
 15. The compound of claim 1, selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof; wherein: Z is(a) hydrogen, deuterium, halo, O, S, N, or Se; (b) Z¹ or Z⁶; or (c)R^(Xc)Z¹, R^(Xc)Z¹, R^(Xa)R^(Xc)Z¹, R^(Xc)Z⁶, R^(Xa)Z⁶, C(R^(Xa)R^(Xb)),or NR^(Xc).
 16. The compound of claim 1, selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof; wherein:R^(x) and R^(Y) are each independently (a) hydrogen, deuterium, azido,cyano, halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a)NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and wherein Z is (a)hydrogen, deuterium, halo, O, S, N, or Se; (b) Z¹ or Z⁶; or (c)R^(Xc)Z¹, R^(Xa)R^(Xc)Z¹, R^(Xc)Z⁶, R^(Xa)R^(Xc)Z⁶, C(R^(Xa)R^(Xb)), orNR^(Xc).
 17. The compound of claim 1, selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof; wherein:R^(X) and R^(Y) are each independently (a) hydrogen, deuterium, azido,cyano, halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)₂R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 18. The composition of claim1, selected from:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable solvates and hydrates thereof; wherein:R^(X) and R^(Y) are each independently (a) hydrogen, deuterium, azido,cyano, halo, nitro, sulfo, —OPO₃H₂, or —PO₃H₂; (b) C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₅ cycloalkyl, C₆₋₂₀ aryl, C₇₋₂₀ aralkyl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a)C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a) —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c)m —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 19. A pharmaceuticalcomposition comprising the compound of claim 1, and a pharmaceuticallyacceptable excipient.
 20. A method of labeling a biomolecule, comprisingthe step of contacting the biomolecule with the compound of claim 1.